Melanocortin-4 receptor binding compounds and methods of use thereof

ABSTRACT

Provided are MC4-R binding compounds of the formula XVII:  
                 
 
     wherein L 2  is a linker group, and P 1 , P 2 , P 3 , P 4 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , t, s, and R are as described in the specification. Methods of using the compounds to treat MC4-R associated disorders, such as disorders associated with weight loss, are also provided.

RELATED APPLICATIONS

[0001] This application is a continuation-in-part of U.S. patentapplication Ser. No. 09/778,468, entitled “Melanocortin-4 ReceptorBinding Compounds and Methods of Use Thereof,” filed on Feb. 7, 2001;which is a continuation-in-part of U.S. patent application Ser. No.09/632,309, entitled “Melanocortin-4 Receptor Binding Compounds andMethods of Use Thereof,” filed on Aug. 4, 2000; which claims priority toU.S. Provisional Application Serial No. 60/223,277, entitled“Melanocortin-4 Receptor Binding Compounds and Methods of Use Thereof,”filed on Aug. 3, 2000; and U.S. Provisional Application Serial No.60/147,288, entitled “Melanocortin-4 Receptor Binding Compounds andMethods of Use Thereof,” filed on Aug. 4, 1999; the entire contents ofall of the aforementioned applications are hereby incorporated herein byreference.

BACKGROUND

[0002] Melanocortins are known to have a broad array of physiologicalactions (Nakanishi, et al. Nature (1979) 278:423-427). Aside from theirwell known effects on adrenal cortical functions and on melanocytes,melanocortins have been shown to affect behavior, learning, memory,control of the cardiovascular system, analgesia, thermoregulation, andthe release of other neurohumoral agents including prolactin,luetinizing hormone, and biogenic amines (De Weid et al. Methods Achiev.Exp. Pathol. (1991) 15:167-199; De Weid et al. Physiol. Rev. (1982)62:977-1059; Gruber, K. A. et al. Am. J. Physiol. (1989) 257:R681-R694;Murphy et al. Science (1980) 210:1247-1249; Murphy et al. Science (1983)221:192-193; Ellerkmann, E. et al. Endocrinol. (1992) 130:133-138;Versteeg, D. H. G. et al. Life Sci. (1986) 835-840). Peripherally,melanocortins have been identified to have immunomodulatory andneurotrophic properties, and to be involved in events surroundingpartition (Cannon, J. G. et al. J. Immunol. (1986) 137:2232-2236;Gispen, W. H. Trends Pharm. Sci. (1992) 11:221-222; Wilson, J. F. Clin.Endocrinol. (1982) 17:233-242; Clark, D. et al. Nature (1978)273:163-164; Silman, R. E. et al. Nature (1976) 260:716-718).Furthermore, melanocortins are present in a myriad of normal humantissues including the brain, ovary, lung, thyroid, liver, colon, smallintestine and pancreas (Tatro, J. B. et al. Endocrinol. (1987)121:1900-1907; Mountjoy, K. G. et al. Science (1992) 257:1248-1251;Chhajlani, V. et al., FEBS Lett. (1992) 309:417-420; Gantz, L. et al.,J. Biol. Chem. (1993) 268:8246-8250; Gantz, L. et al, J. Biol. Chem.(1993) 268:15174-15179).

[0003] Recent studies have described an unexpected diversity of subtypesof receptors for the melanocortin peptides and determined that theybelong to the superfamily of seven transmembrane G-protein linked cellsurface receptors (Mountjoy, K. G. et al., Science(1992), supra;Chhajlani, V. et al., FEBS Lett. (1992), supra). Five melanocortinreceptor subtypes have been cloned. The melanocortin-1 (MC1) receptor isfound in melanoma cells, where it has a role in mediating pigmentation.The melanocortin-2 receptor (MC2-R or ACTH receptor) is found in theadrenal glands where it mediates the effects of ACTH(adrenocorticotrophic hormone). The melanocortin-3 receptor (MC3-R) isprimarily found in the central nervous system (CNS) (Gantz, L. et al.,J. Biol. Chem. (1993) 268:8246-8250), but its physiological function isstill unknown. The melanocortin-4 receptor (MC4-R) has been found in thebrain, where it is widely distributed in several areas, including thecortex, thalamus, hypothalamus, brain stem, and spinal cord (Gantz, L.et al. J. Biol. Chem. (1993) 268:15174-15179; Mountjoy, K. G. et al.Mol. Endocrinol. (1994) 8:1298-1308). MC4-R has recently been related toweight homeostasis. MC4-R “knock out” mice have been shown to developobesity (Huszar et al. Cell (1997) 88:131-141). The feeding behaviorleading to the obesity can be inhibited by injection of MSH peptides(Vergoni et al. Neuropeptides (1986) 7:153-158; Vergoni et al. Eur. J.Pharmacol. (1990) 179:347-355; Fan et al. Nature (1997) 385:165-168).The melanocortin-5 receptor (MC5-R) has a wide peripheral distributionand is believed to participate in the regulation of the exocrine glandfunction (Chen et al. Cell (1997) 91:789-798).

SUMMARY

[0004] In one aspect, the invention pertains to a method for treating amelanocortin-4 receptor (MC4-R) associated state in a mammal. The methodinvolves administering an effective amount of a MC4-R binding compoundto a mammal, such that the MC4-R associated state is treated. The MC4-Rbinding compound is of the formula (I):

B-Z-E  (I)

[0005] wherein B is an anchor moiety, Z is a central moiety, E is aMC4-R interacting moiety, and pharmaceutically acceptable salts,thereof.

[0006] In a further embodiment, the MC4-R binding compound is of theformula (II):

B-A-E  (II)

[0007] wherein B is an anchor moiety, A is cyclic moiety, E is a MC4-Rinteracting moiety, and pharmaceutically acceptable salts, thereof.

[0008] In another embodiment, the invention pertains to another methodfor treating an MC4-R associated state in a mammal, by administering toa mammal an effective amount of a MC4-R binding compound of formula(III):

B-L₁-A-L₂-E  (III)

[0009] wherein B is an anchor moiety, L₁ and L₂ are linking moieties, Ais a cyclic moiety, E is a MC4-R interacting moiety, andpharmaceutically acceptable salts thereof.

[0010] The invention also pertains to treating MC4-R associated stateswith an MC4-R binding compound of formula III, wherein B is substitutedor unsubstituted biaryl, unsubstituted or substituted heterocyclic, orunsubstituted or substituted phenyl, wherein one or more of saidsubstituents are halogens, hydroxy, alkyl, alkynyl, alkoxy, aryl, amino,cyano, or nitro; L₁ is a covalent bond, C₁-C₁₀ branched or unbranchedalkyl, wherein one or two of the carbons are optionally replaced withoxygen, sulfur or nitrogen atoms; L₂ is a covalent bond, substituted orunsubstituted amino, ether, thioether, or alkyl; E is substituted orunsubstituted alkyl, amino, amidino, guanidino, heterocyclic, or aryl,wherein said substituents are amino, arylalkyl, aminoalkyl, alkyl, aryl,alkenyl, or alkynyl; and A is a substituted or unsubstituted phenyl,heteroaryl, cycloalkyl, or biaryl, and pharmaceutically acceptable saltsthereof.

[0011] In another embodiment, the invention pertains to a method fortreating an MC4-R associated state in a mammal by administering aneffective amount of a MC4-R binding compound to a mammal, such that theMC4-R associated state is treated. In this embodiment, the compound isof the formula (IV):

[0012] wherein B is substituted or unsubstituted alkyl, cycloalkyl,alkenyl, alkynyl, aryl, or heteroaryl; A is aryl, heteroaryl, biaryl,cycloalkyl, heterocyclic, or cycloalkenyl; L₁ and L₂ are selected fromthe group consisting of a covalent bond, C₁-C₆ branched or unbranchedalkyl, wherein one or two of the carbons are optionally replaced withoxygen, sulfur or nitrogen atoms; r is a covalent bond, CH, CH₂, CHR¹,CR¹R², or H; t is CH, CH₂, CHR³, CR³R⁴, or H; s is CHR₅, CR⁵, CR⁵R⁶ orabsent (e.g., leaving a non-cyclic diamine); R is H, substituted orunsubstituted alkyl, arylalkyl, or heteroalkyl, and may optionally belinked to A, B, L₁, or L₂; R¹, R², R³, R⁴, R⁵, and R⁶ are eachsubstituted or unsubstituted alkyl, alkenyl, halogen, thiol, thioether,thioalkyl, or alkoxy, and may optionally be linked to form a carbocyclicor heterocyclic ring. Pharmaceutically acceptable salts of the MC4-Rbinding compound are also included.

[0013] The invention also pertains to methods for treating an MC4-Rassociated state in a mammal by administering an effective amount of aMC4-R binding compound of the formula (V):

[0014] wherein B is substituted or unsubstituted biaryl, unsubstitutedor substituted heterocyclic, or unsubstituted or substituted phenyl,wherein one or more of said substituents are halogens, alkyl, alkynyl,alkoxy, aryl, amino, cyano, or nitro; L₁ is a covalent bond, C₁-C₁₀branched or unbranched alkyl, wherein one or two of the carbons areoptionally replaced with oxygen, sulfur or nitrogen atoms; L₂ is acovalent bond, substituted or unsubstituted amino, ether, thioether, oralkyl; E is substituted or unsubstituted alkyl, amino, amidino,guanidino, heterocyclic, or aryl, wherein said substituents are amino,arylalkyl, aminoalkyl, alkyl, aryl, alkenyl, or alkynyl; Π is a covalentbond, a carbon atom, a nitrogen atom, heterocyclic, alkyl, cycloalkyl,or aryl; L₃ is a covalent bond, C₁-C₆ branched, unbranched or cyclicalkyl, wherein one, two or three of the carbons are optionally replacedwith oxygen, sulfur or nitrogen atoms, carbonyl, aminocarbonyl,aminocarbonylamino, aminocarbonyloxy, or aminothiocarbonyl; and Λ isheterocyclic, aryl, alkoxy, amino, alkyl, alkenyl, alkynyl, or hydrogen;and λ is 0, 1 or 2, and pharmaceutically acceptable salts thereof.

[0015] In yet another embodiment, the invention also pertains to amethod for treating an MC4-R associated state in a mammal byadministering an effective amount of a MC4-R binding compound to amammal, wherein the compound is an MC4-R antagonist, and is of theformula (VI):

[0016] wherein

[0017] P¹, P², P³, and P⁴ are optionally substituted carbon, sulfur, ornitrogen, and wherein one of P¹, P², P³ and P⁴ may represent a covalentbond; Z¹, Z², Z³, Z⁴, and Z⁵ are optionally substituted carbon ornitrogen; L₁ is a covalent bond, C₁-C₁₀ branched or unbranched alkyl,wherein one or two of the carbons are optionally replaced with oxygen,sulfur or nitrogen atoms; L₂ is a covalent bond, substituted orunsubstituted amino, ether, thioether, or alkyl; and J is anunsubstituted or substituted nitrogen containing heterocycle or asubstituted or unsubstituted amino group, and pharmaceuticallyacceptable salts thereof.

[0018] In another embodiment, the MC4-R binding compound is of formula(VII):

[0019] wherein

[0020] Z¹, Z², Z³, Z⁴, and Z⁵ are CH, N, or substituted carbon; and

[0021] P¹, P², P³, P⁴, and P⁵ are CH, N or substituted carbon.

[0022] In another embodiment, the MC4-R binding compound is of formula(VIII):

[0023] wherein

[0024] Z¹, Z², Z³, Z⁴, and Z⁵ are CH, N, or substituted carbon; and

[0025] P¹, P², P³, P⁴, and P⁵ are CH, N or substituted carbon.

[0026] The invention also pertains to MC4-R binding compound of theformula (IX):

[0027] wherein:

[0028] P² is CH, CF, CCl, CBr, C-alkyl, C-aryl, C-alkoxy, C—CN, C—OH,CI, or a covalent bond;

[0029] P³ is CH, CF, CCl, CBr, C-alkyl, C-aryl, C-alkoxy, C—CN, C—OH, orCI;

[0030] P⁴ is CH, CCl, CBr, CF, C-alkyl, C-aryl, C-alkoxy, C—CN, C—OH,CI, or a sulfur atom;

[0031] G¹ and G² are each independently CH₂, S, or O;

[0032] r is a covalent bond or CH₂;

[0033] t is CH₂, CHR³, or CR³R⁴;

[0034] s is CH₂, CHR⁵ or CR⁵R⁶;

[0035] R is hydrogen, alkyl, alkoxycarbonyl, or alkylcarbonyl;

[0036] Z¹ is CH, or covalently linked to Z² to form a naphthyl ring;

[0037] Z² is CH, C—(C≡CH), CCl, CBr, CI, CF, or covalently linked to Z¹to form a naphthyl ring;

[0038] Z⁵ is CH, C-alkoxy or C—OMe;

[0039] R³, R⁴, R⁵, and R⁶ are methyl, ethyl, hydroxyl, alkoxy, halogen,cyano, nitro, or amino, or pharmaceutically acceptable salts thereof.

[0040] In still another embodiment the MC4R binding compound is of theformula XVII:

[0041] wherein P¹, P², P³, and P⁴ are each selected from a substitutedor unsubstituted carbon, wherein one of P¹-P⁴ is optionally replaced bya nitrogen atom, or the ring bearing P¹-P⁴ is a thiophene ring, whereinP³-P⁴ together are replaced by a sulfur atom;

[0042] Z¹ is CH or a carbon substituted with R⁷;

[0043] Z² is CH or a carbon substituted with R⁸;

[0044] Z³, Z⁴ and Z⁵ are each independently selected from CH or a carbonsubstituted with R⁹;

[0045] R⁷ is C₁₋₃ alkoxy, C₁₋₃ haloalkoxy, cyano, C₁₋₃ cyanoalkyl, halo,C₁₋₃ alkyl, or C₁₋₃ haloalkyl;

[0046] R⁸ is halo, C₁₋₃ alkyl, C₁₋₃ haloalkyl, or R⁷ and R⁸ areoptionally taken together with their intervening atoms to form a fused,5-6 membered aromatic or nonaromatic ring having 0-2 ring heteroatomsselected from oxygen, nitrogen or sulfur;

[0047] each R⁹ is independently selected from halo, cyano,trialkylsiloxy, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, C₁₋₆ alkynyl, N(R¹⁰)₂, (C₁₋₆ alkyl)-N(R¹⁰)₂, O(C₁₋₆alkyl)-N(R¹⁰)₂, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylthio, or phenyl;

[0048] Each R¹⁰ is independently selected from hydrogen, C₁₋₄ alkyl, ortwo R¹⁰ on the same nitrogen are taken together with their interveningnitrogen to form a 5-6 membered ring having 1-2 ring heteroatomsselected from oxygen, nitrogen or sulfur;

[0049] L₂ is a covalent bond, a substituted or an unsubstituted 1-2carbon chain or a 2 carbon carbonyl chain, wherein one of the carbonsalong with the hydrogen attached thereto is optionally replaced byoxygen, N(R¹⁰), or sulfur;

[0050] t is CH₂, CHR³, or CR³R⁴, and s is CH₂, CHR⁵, or CR⁵R⁶, or t-staken together is CH═CH, CR³═CH, CH═CR⁵ or CR³═CR⁵;

[0051] R³, R⁴, R⁵, and R⁶ are each independently selected from C₁₋₄alkyl, C₁₋₄ alkylcarboxyl, C₁₋₄ alkylcarboxamide, or two of R³, R⁴, R⁵,and R⁶ are taken together with their intervening atom or atoms to form afused 3-7 membered aromatic or non-aromatic or 3-7 membered spirocyclicring, having 0-2 ring heteroatoms selected from oxygen, nitrogen orsulfur;

[0052] R is hydrogen or a C₁₋₈ alkyl or C₁₋₈ alkylcarbonyl that issubstituted with 0-2 R¹¹, or R and R⁵ are taken together with theirintervening atoms to form a fused pyrrolidino or piperidino ring, or Rand L₂ are taken together with their intervening atoms to form a fusedfive membered ring having 1-2 ring heteroatoms selected from oxygen,nitrogen or sulfur;

[0053] each R¹¹ is independently selected from C₁₋₃ alkyl, cyano, halo,haloalkyl, N(R¹⁰)₂, (C═O)N(R¹⁰)₂, OC(═O)N(R¹⁰)₂, OH, S(C₁₋₆ alkyl),SO₂(C₁₋₆ alkyl), SO₂N(R¹⁰)₂, C₁₋₆ alkoxy, C₁₋₆ alkylcarbonyl, C₁₋₆alkylcarboxyl, C₁₋₆ alkoxycarboxyl, C₅₋₆ aryl, C₆₋₁₀ arylalkyl, or a 3-6membered heterocyclyl having 1 or 2 heteroatoms;

[0054] or a pharmaceutically acceptable salt thereof.

[0055] The invention also features a pharmaceutical composition for thetreatment of a MC4-R associated state in a mammal. The pharmaceuticalcompositions contain a pharmaceutically acceptable carrier and a MC4-Rbinding compound. The compounds are described herein in the context ofthe description of the method but it should be understood that theinvention further pertains to pharmaceutical compositions containing thecompounds and the compounds per se. For example, pharmaceuticalcompositions of the invention include a pharmaceutically acceptablecarrier and an effective amount of at least one MC4-R binding compoundof the formula (I):

B-Z-E  (I)

[0056] wherein B is an anchor moiety, Z is an central moiety, E is aMC4-R interacting moiety, and pharmaceutically acceptable salts thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

[0057]FIGS. 1a and 1 b are bar graphs showing the effects of MT II (aMC4-R agonist) on food intake in lean mice.

[0058]FIG. 2 is a graph depicting the effects of treating lean mice withCompound N and MT II on food intake over a six hour period.

[0059]FIG. 3 is a graph depicting the effects of treating lean mice withCompound O and MT II on food intake over a six hour period.

DETAILED DESCRIPTION OF THE INVENTION

[0060] In one aspect, the invention pertains to a method for treating amelanocortin-4 receptor (MC4-R) associated state in a mammal. The methodinvolves administering an effective amount of a MC4-R binding compoundto a mammal, such that the MC4-R associated state is treated. The MC4-Rbinding compound is of the formula (I):

B-Z-E  (I)

[0061] wherein B is an anchor moiety, Z is a central moiety, E is aMC4-R interacting moiety, and pharmaceutically acceptable salts thereof.

[0062] The term “MC4-R” includes receptors for α-melanocyte stimulatinghormone. The MC4-R is usually found in the brain where it is widelydistributed (Mountjoy et al. Mol. Endocrinol. (1994) 8:1298-1308).Melanocortins are peptide hormones that play an important role inregulating melanocyte pigmentation as well as memory andthermoregulation. They consist of various peptides, such as α-melanocytestimulating hormone, that are cleaved from the polypeptide precursorprooptiomelanocortin (POMC). The effects of melanocortins are mediatedvia stimulation of adenylate cyclase via the activation of themelanocortin receptors.

[0063] The melancortin-4 receptor (MC4-R) is a G-protein coupledreceptor (GPCR) expressed in brain tissue. The specific role of theMC4-R protein in vivo was investigated by engineering MC4-R “knock out”mice. The mice were unable to produce functional MC4-R protein, becausethe endogenous MC4-R gene coding sequence was deleted.

[0064] The knock-out mice were produced by using human MC4-r genesequences to isolate and clone the murine MC4-r gene. A murine MC4-rtargeting construct was then generated which was designed to delete themajority of the murine MC4-r coding sequence upon homologousrecombination with the endogenous murine MC4-r gene. Embryonic stem (ES)cells containing the disrupted MC4-r gene were produced, isolated andmicroinjected into murine blastocysts to yield mice chimeric for cellscontaining a disrupted MC4-r gene. Offspring of the chimeric miceresulting from germline transmission of the ES genome were obtained andanimals heterozygous for the disrupted MC4-R were identified.

[0065] To assess the role of MC4-R in vivo, the animals heterozygous forthe MC4-r disrupted gene were bred together, producing litterscontaining wild-type mice, mice heterozygous for the MC4-r mutation andmice homozygous for the MC4-R mutation. The weight gain of the animalswas monitored regularly. Homozygous null MC4-R mutants showed anincrease in weight compared to mice heterozygous for MC4-R deletion andwild type mice as early as 25 days of age. By 54-58 days of age, MC4-Rdeficient mice exhibited, on average, a 55-70% greater weight relativeto wild type mice, and an approximately 50% greater weight compared tomice heterozygous for the MC4-R deletion.

[0066] The language “MC4-R associated states” includes those states,disorders, or diseases characterized by aberrant or undesirable activityor expression of MC4-Rs. It also includes those states, disorders anddiseases associated with MC4-R ligands (e.g., α-melanocyte stimulatinghormone). The language also includes prevention of states, disorders anddiseases characterized by aberrant or undesirable activity of MC4-Rs orits ligands. Examples of MC4-R associated states include, but are notlimited to, disorders involving or associated with pigmentation, bones,pain, and weight homeostasis, e.g., weight loss or obesity. MC4-Rassociated states include the unhealthy decrease in body weight that canoccur during an acute inflammatory response or that occurs in a cancerpatient as a result of cachexia, radiotherapy or chemotherapy, or to theundesirable decrease in body mass due to simulated or actualweightlessness, such as occurs during space travel.

[0067] Other examples of unhealthy decreases in weight occur in somepatients during advance stages of illnesses such as AIDS.Physiologically, this may be a result from any one of a number ofcomplex factors, such as loss of appetite and possibly abnormalcatabolism. This cachexia, may be slowed by MC4-R binding compounds. Ina preferred embodiment of the invention, the weight loss is a result ofold age (e.g., sarcopenia or age associated involuntary weight loss),anorexia nervosa, or cachexia (e.g., cachexia associated with cancer orHIV).

[0068] Examples of MC4-R associated disorders include feeding andwasting disorders, such as cachexia (e.g., chronic disease associatedcachexia including cancer cachexia, AIDS cachexia, CHF cachexia, etc.),anorexia, catabolic wasting, aging associated involuntary weight loss,and sarcopenia. Recent studies have demonstrated that the centralmelanocortin signaling system, in particular MC4-R contributes to animalmodels of cachexia. Wisse B E, et al. Endocrinology 142:3292-3301(2001); Marks D L, et al. Cancer Res 61:1432-1438 (2001); Vergoni A V,et al. Eu J Pharm 369:11-15 (1999).

[0069] Cachexia is a common pathological syndrome associated with cancerand other chronic illnesses (e.g., AIDS, chronic heart failure, chronicinfection, etc), which encompasses both the loss of appetite and theinability to conserve energy. A hallmark of the disorder is loss of fatand lean body mass, contributing to morbidity, mortality, and reducedquality of life in afflicted patients. Ronald M. L. and J. B. Tatro,Diabetes, 8: 267-271, (1999); Tisdale M J Nutrition 17: 438-442 (2001).Physiologically, this may be a result from any one of a number ofcomplex factors, such as loss of appetite and possibly abnormalcatabolism.

[0070] Sarcopenia is a generic term for failure to thrive (e.g., due toloss of lean body mass, in particular skeletal muscle mass) that occurswith age. For example, loss of muscle mass, quality, and strength canultimately contribute and lead to frailty in the elderly.

[0071] Accordingly the instant invention provides compounds,compositions, and methods effective for increasing feeding behavior andbody weight, which are particularly useful in treating those disordersor diseases associated with weight loss and wasting (e.g., cachexia(e.g., chronic disease associated cachexia including cancer cachexia,AIDS cachexia, CHF cachexia, etc.), anorexia, catabolic wasting, agingassociated involuntary weight loss, and sarcopenia.

[0072] In one further embodiment, the MC4-R associated state is notweight loss.

[0073] In an embodiment, the MC4-R associated disorder is a boneassociated disorder. MC4-R knockout mice have been shown to haveenhanced bone thickness (Ducy et al. Science, (September, 2000)289:1501-1504). Examples of bone associated disorders which may betreated with MC4-R binding compounds of the invention include disordersand states where the formation, repair or remodeling of bone isadvantageous. For examples bone associated states include osteoporosis(e.g., a decrease in bone strength and density), bone fractures, boneformation associated with surgical procedures (e.g., facialreconstruction), osteogenesis imperfecta (brittle bone disease),hypophosphatasia, Paget's disease, fibrous dysplasia, osteopetrosis,myeloma bone disease, and the depletion of calcium in bone, such as thatwhich is related to primary hyperparathyroidism. Bone associateddisorders include all states in which the formation, repair orremodeling of bone is advantageous to the subject as well as all otherdisorders associated with the bones or skeletal system of a subjectwhich can be treated with the compounds of the invention.

[0074] Melanocortins increase neuropathic pain in animal models andantagonize opiate analgesia, and antagonists counteract neuropathicpain. Vrinten D H, et al. J Neurosci 20:8131-8137 (2000); Adan R A H inThe melanocortin receptors. Cone R D, ed. Totowa, N.J.: Humana Press;109-141 (2000). Additionally, patients with cancer might have theadditional benefit of improved pain control when treated withmelanocortin receptor antagonists undergoing a cancer cachexia treatmentregimen. Thus, the methods and compositions described herein may beuseful in the treatment of MC4-R associated pain or neuronal disorders,including neuropathic pain.

[0075] The term “mammal” includes organisms which express the MC4-R.Examples of mammals include mice, rats, cows, sheep, pigs, goats,horses, bears, monkeys, dogs, cats and, preferably, humans. Transgenicorganisms which express the MC4-R are also included in this definition.

[0076] The language “MC4-R binding compound” includes those compoundswhich interact with the MC4-R resulting in modulation of the activity ofthe MC4-R. In an embodiment, the MC4-R binding compounds are antagonistsof the MC4-R. The term “antagonist” includes compounds which interactwith the MC4-R and modulate, e.g., inhibit or decrease, the ability of asecond compound, e.g., α-melanocyte stimulating hormone or another MC4-Rligand, to interact with the MC4-R. In another embodiment, the MC4-Rbinding compounds is an agonist of the MC4-R. The term “agonists”includes compounds which interact with the MCR-4 and modulate, e.g.,increase or stimulate, its activity and/or its ability to interact witha second compounds, e.g., α-melanocyte stimulaturing hormone.

[0077] MC4-R binding compounds can be identified through both in vitro(e.g., cell and non-cell based) and in vivo methods. These methods aredescribed in detail in Examples 4, 5, 6, and 7.

[0078] The Scincillation Proximity Assay (SPA) is a non-cell based invitro assay, described in Example 4. It can be used to identifycompounds that interact with, e.g., bind to MC4-R. Such compounds mayact as antagonists or agonists of MC4-R activity and may be used in thetreatment of body weight disorders. One example of a qualitative measureof binding affinity of a MC4-R binding compound to MC4-R is its IC₅₀Preferably, the MC4-R binding compound binds to the MC4-R with a bindingaffinity, for example, of about 50 μM or less, 20 μM or less, 10 μM orless, 5 μM or less, 2.5 μM or less, or 1 μM or less. In an advantageousembodiment, the IC₅₀ of a MC4-R binding compounds is about 0.5 μM orless, about 0.3 μM or less, about 0.1 μM or less, about 0.08 μM or less,about 0.06 μM or less, about 0.05 μM or less, about 0.04 μM or less, or,preferably, about 0.03 μM or less.

[0079] In the SPA, isolated membranes are used to identify compoundsthat interact with MC4-R. For example, in a typical experiment usingisolated membranes, 293 cells may be genetically engineered to expressthe MC4-R. Membranes are be harvested by standard techniques and used inan in vitro binding assay. ¹²⁵I-labeled ligand (e.g., ¹²⁵I-labeledα-MSH, β-MSH, or ACTH) is bound to the membranes and assayed forspecific activity; specific binding is determined by comparison withbinding assays performed in the presence of excess unlabelled ligand.

[0080] To identify MC4-R binding compounds, membranes are incubated withlabeled ligand in the presence or absence of test compound. Compoundsthat bind to the receptor and compete with labeled ligand for binding tothe membranes reduced the signal compared to the vehicle controlsamples. Preferably, the screens are designed to identify compounds thatantagonize the interaction between MC4-R and MC4-R ligands such asα-MSH, β-MSH and ACTH. In such screens, the MC4-R ligands are labeledand test compounds can be assayed for their ability to antagonize thebinding of labeled ligand to MC4-R.

[0081] Cell based assay systems can also be used to identify MC4-Rbinding compounds. An example of a cell based assay system is the cAMPassay described in detail in Example 5. Cell based methods may use cellsthat endogenously express MC4-R for screening compounds which bind toMC4-R. Alternatively, cell lines, such as 293 cells, COS cells, CHOcells, fibroblasts, and the like, genetically engineered to express theMC4-R can also be used for screening purposes. Preferably, host cellsgenetically engineered to express a functional receptor that responds toactivation by melanocortin peptides can be used as an endpoint in theassay; e.g., as measured by a chemical, physiological, biological, orphenotypic change, induction of a host cell gene or a reporter gene,change in cAMP levels, adenylyl cyclase activity, host cell G proteinactivity, extracellular acidification rate, host cell kinase activity,proliferation, differentiation, etc.

[0082] To be useful in screening assays, the host cells expressingfunctional MC4-R should give a significant response to MC4-R ligand,preferably greater than 5-fold induction over background. Host cellsshould preferably possess a number of characteristics, depending on thereadout, to maximize the inductive response by melanocortin peptides,for example, for detecting a strong induction of a CRE reporter gene:(a) a low natural level of cAMP, (b) G proteins capable of interactingwith the MC4-R, (c) a high level of adenylyl cyclase, (d) a high levelof protein kinase A, (e) a low level of phosphodiesterases, and (f) ahigh level of cAMP response element binding protein would beadvantageous. To increase response to melanocortin peptide, host cellscould be engineered to express a greater amount of favorable factors ora lesser amount of unfavorable factors. In addition, alternativepathways for induction of the CRE reporter could be eliminated to reducebasal levels.

[0083] In using such cell systems, the cells expressing the melanocortinreceptor are exposed to a test compound or to vehicle controls (e.g.,placebos). After exposure, the cells can be assayed to measure theexpression and/or activity of components of the signal transductionpathway of the melanocortin receptor, or the activity of the signaltransduction pathway itself can be assayed. For example, after exposure,cell lysates can be assayed for induction of cAMP. The ability of a testcompound to increase levels of cAMP, above those levels seen with cellstreated with a vehicle control, indicates that the test compound inducessignal transduction mediated by the melanocortin receptor expressed bythe host cell. In screening for compounds that may act as antagonists ofMC4-R, it is necessary to include ligands that activate the MC4-R, e.g.,α-MSH, β-MSH or ACTH, to test for inhibition of signal transduction bythe test compound as compared to vehicle controls.

[0084] When it is desired to discriminate between the melanocortinreceptors and to identify compounds that selectively agonize orantagonize the MC4-R, the assays described above may be conducted usinga panel of host cells, each genetically engineered to express one of themelanocortin receptors (MC1-R through MC5-R). Expression of the humanmelanocortin receptors is preferred for drug discovery purposes. To thisend, host cells can be genetically engineered to express any of theamino acid sequences shown for melanocortin receptors 1 through 5. Thecloning and characterization of each receptor has been described: MC1-Rand MC2-R (Mountjoy., 1992, Science 257: 1248-1251; Chhajlani & Wikberg,1992 FEBS Lett. 309: 417-420); MC3-R (Roselli-Rehfuss et al., 1993,Proc. Natl. Acad. Sci., USA 90: 8856-8860; Gantz et al., 1993, J. Biol.Chem. 268: 8246-8250); MC4-R (Gantz et al., 1993, J. Biol. Chem. 268:15174-15179; Mountjoy et al., 1994, Mol. Endo. 8: 1298-1308); and MC5-R(Chhajlani et al., 1993, Biochem. Biophys. Res. Commun. 195: 866-873;Gantz et al., 1994, Biochem. Biophys. Res. Commun. 200; 1234-1220), eachof which is incorporated by reference herein in its entirety. Thus, eachof the foregoing sequences can be utilized to engineer a cell or cellline that expresses one of the melanocortin receptors for use inscreening assays described herein. To identify compounds thatspecifically or selectively regulate MC4-R activity, the activation, orinhibition of MC4R activation is compared to the effect of the testcompound on the other melanocortin receptors. In certain embodiments, itmay be advantageous to select compounds of the invention selective forMC4-R, or, alternatively, it may be useful to select compounds whichinteract with other receptors as well.

[0085] In one further embodiment, the MC4-R binding compounds of theinvention are more selective for the MC4-R than at least one other MCreceptors, for example, more than twice as selective, at least ten timesas selective, at least twenty times as selective, at least fifty timesas selective, or at least one hundred times as selective.

[0086] In one further embodiment, the MC4-R binding compounds of theinvention are more selective for the MC4-R than the MC1-R, for example,more than twice as selective, at least ten times as selective, at leasttwenty times as selective, at least fifty times as selective, or atleast one hundred times as selective.

[0087] In one further embodiment, the MC4-R binding compounds of theinvention are more selective for the MC4-R than the MC3-R, for example,more than twice as selective, at least ten times as selective, at leasttwenty times as selective, at least fifty times as selective, or atleast one hundred times as selective.

[0088] In one further embodiment, the MC4-R binding compounds of theinvention are more selective for the MC4-R than the MC5-R, for example,more than twice as selective, at least ten times as selective, at leasttwenty times as selective, at least fifty times as selective, or atleast one hundred times as selective.

[0089] In yet another further embodiment, the MC4-R binding compounds ofthe invention are more selective for the MC4-R receptor than at leastone, two or three other MC receptors (such as, for example, MC1-R,MC3-R, or MC5-R). In a further embodiment, the MC4-R binding compoundsare more selective for the MC4-R than MC1-R, MC3-R, and MC5-R. In afurther embodiment, the MC4-R binding compounds as at least ten times asselective, at least twenty times as selective, at least fifty times asselective, or at least one hundred times as selective for the MC4-R thanthe MC1-R, MC3-R and the MC5-R.

[0090] As stated above, in an embodiment, the MC4-R binding compoundincludes compounds of the formula (I):

B-Z-E  (I)

[0091] wherein B is an anchor moiety, Z is a central moiety, E is aMC4-R interacting moiety, and pharmaceutically acceptable salts thereof.

[0092] The language “anchor moiety” (“B”) includes moieties whichinteract with the MC4-R, which may, advantageously, result in thebinding of the MC4-R binding compound to the MC4-R. Examples of anchormoieties include substituted or unsubstituted alkyl (e.g., branched,straight chain, or cyclic (e.g., cyclohexane, cyclopentane)), alkenyl,alkynyl, aryl (e.g., substituted or unsubstituted phenyl, naphthyl,biphenyl, anthracenyl, fluorenyl, etc.), heterocyclic (e.g., thienyl,morpholinyl, piprazinyl, piperidinyl, etc.), and multicyclic (e.g.,indolyl, benzothioenyl, etc.) moieties. Other examples of anchormoieties include carbonyl moieties, thiol groups, cyano groups, aminogroups, and hydrogen atoms.

[0093] In a further embodiment, the anchor moiety (“B”) includessubstituted or unsubstituted carbocyclic aryl moieties, e.g., phenyl,naphthyl, etc. Examples of substituents include halogens (e.g.,fluorine, chlorine, iodine, bromine, etc.), alkoxy (e.g., methoxy,ethoxy, isopropoxy, n-propyloxy, n-butyloxy, pentoxy, cyclopentoxy,arylalkyloxy, etc.) hydroxy, alkylcarbonyl, cyano, nitro, thiol,thioether, thioalkyl, alkenyl, alkynyl (e.g., ethynyl, etc.),alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkoxycarbonyl, aminocarbonyl,alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino (includingalkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino),acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyland ureido), amidino, imino, sulfhydryl, alkylthio, arylthio,thiocarboxylate, sulfates, sulfonato, sulfamoyl, sulfonamido,trifluoromethyl, azido, heterocyclyl, alkylaryl, heteroaryl, alkyl(e.g., unsubstituted (e.g., methyl, ethyl, propyl, butyl, hexyl, etc.)or substituted, e.g., halogen substituted, e.g., trifluoromethyl,trichloromethyl), aryl (e.g., substituted and unsubstituted phenyl,heteroaryl (e.g., thienyl, pyridinyl, etc.), arylalkyl, arylalkenyl,arylalkynyl, or combinations thereof. In yet another further embodiment,the anchor moiety substituent can be substituted itself with one or morehalogen, nitro, alkyl, alkenyl, alkynyl, aryl or alkoxy groups, orcombinations thereof. In certain embodiments, the aryl moiety is fusedto another ring which can be substituted or unsubstituted, carbocyclicor heterocyclic, aromatic or non-aromatic.

[0094] In a further embodiment, the anchor moiety is substituted with atleast one halogen, alkoxy group, or alkyl (e.g., substituted orunsubstituted) group. Examples of halogen substituted phenyl anchormoieties include o-iodophenyl, m-iodophenyl, o-bromophenyl,m-bromophenyl, o-chlorophenyl, m-chlorophenyl, o-fluorophenyl,m-fluorophenyl, p-fluorophenyl, m-nitrophenyl, or o-methoxy. The anchormoiety may also comprise more than one substituent, e.g. two halogens,e.g., two fluorines, a fluorine and a chlorine. Other examples of anchormoieties include 2-methoxy-5-bromophenyl, 2-methoxy-5-fluorophenyl,2-methoxy-5-iodophenyl, 2-methoxy-5-fluorophenyl,2-ethoxy-5-bromophenyl, 2-methoxy-6-bromophenyl,3-methoxy-6-bromophenyl, 2-isopropyl-5-bromophenyl,2-n-propyl-5-bromophenyl, and 2-cyclopentyloxy-5-bromophenyl.

[0095] Other examples of anchor moieties include, but are not limitedto, 2-methoxy-5-cyanophenyl, 2-chloro-5-chlorophenyl,2-methoxy-6-methoxyphenyl, 2-methoxy-5-nitrophenyl, 2-methoxy-5-phenylphenyl, 2-methoxy-5-3′-thiofuranyl phenyl, 2-methoxy-5-methylcarbonylphenyl, 3,5-dimethyloxy phenyl, 2-methoxyphenyl, 2,5-dimethoxy phenyl,2-fluoro-6-chlorophenyl, and 3-chloro-4-fluorophenyl.

[0096] In another further embodiment, the anchor moiety includessubstituted and unsubstituted heterocycles. Examples of suchheterocycles include, but are not limited to, furanyl, imidazolyl,benzothiophenyl, benzofuranyl, quinolinyl, isoquinolinyl, benzodiozanyl,benzoxazolyl, benzothiazolyl, methylenedioxyphenyl, ethylenedioxyphenyl,indolyl, thienyl, pyrimidyl, pyrazinyl, purinyl, deazapurinyl,morpholine, piprazine, piperidine, thiomorpholine, and thioazolidine.Examples of substituents include alkyl (e.g., substituted orunsubstituted, branched straight chain or cyclic, e.g., methyl, ethyl,propyl, butyl, pentyl, etc.), alkenyl, alkynyl, halogens (e.g.,fluorine, chlorine, bromine, iodine, etc.), hydroxyl, alkoxy,alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl,aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato,cyano, amino (including alkyl amino, dialkylamino, arylamino,diarylamino, and alkylarylamino), acylamino (includingalkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino,imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates,sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, azido,heterocyclyl, alkylaryl, aryl and heteroaryl groups.

[0097] In another further embodiment, the anchor moiety (“B”) is asubstituted or unsubstituted fused aryl or biaryl moiety. Biarylmoieties include moieties with two or more aromatic rings, which may befused or connected through one or more covalent bonds. Examples includebiphenyl, fluorene, anthracenyl, benzoquinazolinyl, and naphthyl.Examples of substituents of biaryl moieties include alkyl (e.g.,substituted and unsubstituted, branched or straight chain, methyl,ethyl, propyl, butyl, pentyl, etc.), alkoxy (e.g., methoxy, ethoxy,propoxy, butoxy, pentoxy, cyclopentoxy, etc.), alkenyl, alkynyl,hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl,aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato,amino (including alkyl amino, dialkylamino, arylamino, diarylamino, andalkylarylamino), acylamino (including alkylcarbonylamino,arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl,alkylthio, arylthio, thiocarboxylate, sulfates, sulfonato, sulfamoyl,sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl,alkylaryl, an aromatic heteroaromatic moiety, halogens (e.g., fluorine,.chlorine, bromine, iodine, etc.), combinations thereof and other groupswhich allow the MC4-R binding compound to perform its intended function.Biaryl moieties also include moieties which comprise one or moreheterocycles, such as, benzothiofuranyl, benzothienyl, quinolinyl,benzothiophenyl, benzofuranyl, isoquinolinyl, benzodiozanyl,benzoxazolyl, benzothiazolyl, methylenedioxyphenyl, ethylenedioxyphenyl,and indolyl. Examples of biaryl anchor moieties include naphthyl,2-methoxynaphthyl, 2-methoxy-5-phenyl phenyl, 2-ethoxynaphthyl,2-methoxy-5-thiofuranyl phenyl, 2-methyl naphthyl, 2-n-propyl naphthyl,benxothiofuranyl, 2-phenyl phenyl, 2-methoxy-5-4′methoxy-phenyl phenyl;2-methoxy-5-(3′-fluoro-4′-phenyl) phenyl phenyl; 2-cyclopentoxynaphthyl;quinolinyl; and 2-methoxy-5-(3′-chloro-4′fluoro)phenyl phenyl.

[0098] Furthermore, the anchor moiety can be multicyclic and comprise acombination of one or more aromatic, non-aromatic, heterocyclic, andheteroaryl rings, which can be fused, bridged, or linked togetherthrough covalent bonds. The multicyclic anchor moiety may also besubstituted with substituents such as alkyl (e.g., substituted orunsubstituted, branched straight chain or cyclic, e.g., methyl, ethyl,propyl, butyl, pentyl, etc.), alkenyl, alkynyl, halogens (e.g.,fluorine, chlorine, bromine, iodine, etc.), hydroxyl, alkoxy,alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl,aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato,cyano, amino (including alkyl amino, dialkylamino, arylamino,diarylamino, and alkylarylamino), acylamino (includingalkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino,imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates,sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, azido,heterocyclyl, alkylaryl, aryl and heteroaryl groups.

[0099] The term “central moiety” (“Z”) includes moieties whichcovalently attach the anchor moiety to the MC4-R interacting moiety.Examples of central moieties include cyclic moieties, optionallysubstituted amines (e.g., tertiary amino, aminoalkylamino,dialkylaminoalkylamino, aminocarbonylamino, aminocarbonylamino;arylaminocarbonylamino groups; arylaminothiocarbonylamino), optionallysubstituted alkyl groups (e.g., carbon atoms with substituted orunsubstituted alkyl, aryl (e.g., phenyl, naphthyl), heterocyclicmoieties (e.g., morpholinyl, piprazinyl, etc.), and carbonyl groups,etc. Examples of substituents of the central moiety include, forexample, alkyl (e.g., straight, branched or cyclic, substituted orunsubstituted, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl), alkenyl (ethenyl, propenyl, butenyl, etc.),alkynyl (e.g., ethynyl, propynyl, etc.), halogen (e.g., chlorine,fluorine, iodine, bromine), hydroxyl, alkoxy (e.g., methoxy, ethoxy,trifluoromethoxy, trichloromethoxy, propoxy, butoxy, cyclopropoxy,etc.), alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl,aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato,cyano, amino (including alkyl amino, arylalkylamino, dialkylamino,arylamino, diarylamino, and alkylarylamino), acylamino (includingalkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino,imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates,sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, azido,heterocyclyl (e.g., morpholinyl, piprazinyl, etc.), arylalkyl, alkylaryland aryl (e.g., substituted or unsubstituted phenyl (e.g., alkyl,halogen, alkoxy substituted), naphthyl, anthracene, etc.) and heteroarylmoieties. Furthermore, the central moiety may further comprise one ormore linking moieties. For example, the linking moieties may covalentlylink the cyclic moiety to the anchor moiety and/or the MC4-R interactingmoiety.

[0100] The term “central moiety” also includes moieties of the formula(XII):

[0101] wherein

[0102] Π is a covalent bond, a carbon atom, a nitrogen atom,heterocyclic, alkyl, carbocyclic, or aryl;

[0103] L₃ is a covalent bond, C₁-C₆ branched, unbranched or cyclicalkyl(wherein one, two or three of the carbons are optionally replacedwith oxygen, sulfur or nitrogen atoms), carbonyl, aminocarbonyl,aminocarbonylamino, aminocarbonyloxy, or aminothiocarbonyl moiety;

[0104] Λ is substituted or unsubstituted heterocyclic, aryl, alkoxy,amino, alkyl, alkenyl, alkynyl, or hydrogen; and

[0105] λ is 0, 1 or 2.

[0106] In a further embodiment, Π is a carbon or nitrogen atom. In otherembodiments, Π is alkyl, carbocyclic, heterocyclic (e.g., piprazinyl,morphonlinyl, piperidinyl, etc.).

[0107] In another further embodiment, Λ is heterocyclic (e.g.,non-aromatic, e.g., substituted or unsubstituted, bridged, fused, ormonocyclic, morpholinyl, piperidinyl, azetidinyl, piprazinyl, etc. oraromatic, e.g., pyridinyl, pyrimidinyl, pyrrolyl, etc.), aryl e.g.,phenyl, naphthyl) or amino (e.g., substituted or unsubstituted, e.g.,alkylamino, dialkyl amino, etc.).

[0108] The language “cyclic moiety” includes heterocyclic andcarbocyclic groups, such as substituted or unsubstituted phenyl,heteroaryl, or biaryl moieties. Examples of cyclic moieties includethose without aromaticity (e.g., cyclohexane, cyclopentane, etc.) andthose with aromaticity, e.g. moieties that have at least one aromaticring. Cyclic moieties may include one or more heteroatoms. Examplesinclude phenyl, pyrrole, furan, thiophene, imidazole, benzoxazole,benzothiazole, triazole, tetrazole, pyrazole, pyridine, pyrazine,pyridazine, pyrimidine, naphthyl, quinolyl, indolyl, and the like. Thecyclic moiety can be substituted at one or more ring positions with suchsubstituents such as, for example, alkyl (e.g., substituted orunsubstituted methyl, ethyl, propyl, butyl), alkenyl (ethenyl, propenyl,butenyl, etc.), alkynyl (e.g., ethynyl, propynyl, etc.), halogen (e.g.,chlorine, fluorine, iodine, bromine), hydroxyl, alkoxy (e.g., methoxy,ethoxy, trifluoromethoxy, trichloromethoxy, propoxy, butoxy,cyclopropoxy, etc.), aryloxy, alkylcarbonyloxy, arylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate,phosphonato, phosphinato, cyano, amino (including alkyl amino,dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,sulfates, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl,azido, heterocyclyl, alkylaryl, and aryl (e.g., substituted orunsubstituted phenyl, naphthyl) and heteroaryl moieties. The cyclicmoiety can also be fused or bridged with alicyclic or heterocyclic ringswhich are not aromatic so as to form a polycycle (e.g., tetralin, orfluorene).

[0109] In an embodiment, the cyclic moiety of the present invention issubstituted or unsubstituted phenyl, heteroaryl, or biaryl. The language“cyclic moiety” also includes non-aromatic cyclic moieties, such as,substituted or unsubstituted cyclic alkanes, (e.g., cyclohexane, andcyclopentane), cyclic alkenes (e.g., cyclohexene), and substituted orunsubstituted heterocycles (e.g., thiofuran, pyrimidine, pyrazine,pyrrole, imidazole, quinoxaline, etc.). The language “cyclic moiety”comprises not only the heterocyclic or carbocyclic moieties, but alsomay additionally include moieties which further comprise linkingmoieties, such as L₁ and L₂ which, for example, may link the anchormoiety to the carbocyclic or heterocyclic cyclic portion of the cyclicmoiety. Furthermore, linking moieties may also link the heterocyclic orcarbocyclic cyclic moiety to the MC4-R interacting moiety. Examples ofcyclic moieties include unsubstituted phenyl, halogenated phenyl (e.g.,fluoro, bromo, chloro and iodo phenyl), alkyl substituted phenyl (e.g.,methyl, ethyl, propyl, etc.),amino substituted phenyl, heteroaryls(e.g., thiofuran, pyridine, quinoxaline, pyrazine, pyrrole, etc.).

[0110] The language “MC4-R interacting moiety” (“E”) includes moietieswhich permit the MC4-R binding compound to perform its intendedfunction, e.g., interact with the MC4-R. Examples of MC4-R interactingmoieties include substituted or unsubstituted alkyl (e.g., substitutedwith amino, cyano, nitro, hydroxy, etc.), aryl (e.g., phenyl,heteroaryl), amino (e.g., 3-aminopropylamino, dimethyl amino, diethylamino), amidino, guanidino, carbocyclic and heterocyclic moieties. Thelanguage “MC4-R interacting moiety” is not intended to suggest that thismoiety is the active pharmacophore of the molecule, responsible for thepharmacological, binding or other properties of the MC4-R bindingcompound.

[0111] In one embodiment, the MC4-R interacting moiety is cyclic, e.g.,aryl, alkyl, biaryl, polycyclic, heteroaromatic, or heterocyclic.Examples of heterocyclic MC4-R interacting moieties include heterocycleswhich contain nitrogen atoms, such as, substituted and unsubstitutedimidazolyl, imidazolinyl, pyridinyl, pyrrolyl, piprazinyl,imidoazopyridinyl, pyrolloimidazolyl, pyrrolyl, azetidinyl, azapanyl,pyrimidinyl, pyridinyl, morpholinyl, diazapanyl, and piperidinylmoieties. The MC4-R interacting moiety may be bicyclic, polycyclic,bridged or a fused ring system. Examples of fused and bridgedheterocycles include:

[0112] The substituent R includes substituted and unsubstituted alkyl(e.g., methyl, ethyl, etc.), arylcarbonyl, alkoxycarbonyl,alkylcarbonyl, arylalkylcarbonyl, and other groups which allow the MC4-Rinteracting moiety to perform its intended function.

[0113] The MC4-R interacting moiety can be substituted with substituentssuch as, but not limited to, halogens (e.g., fluorine, chlorine,bromine, iodine, etc.), alkyl (e.g., substituted or unsubstituted,branched straight chain or cyclic, e.g., methyl, ethyl, propyl, butyl,pentyl, etc.), alkenyl, alkynyl, hydroxyl, alkoxy, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl,phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, aminoalkyl, andalkylarylamino), acylamino (including alkylcarbonylamino,arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl,alkylthio, arylthio, thiocarboxylate, sulfates, sulfonato, sulfamoyl,sulfonamido, nitro, trifluoromethyl, azido, heterocyclyl, alkylaryl,aryl, heteroaryl moieties and combinations thereof.

[0114] In another embodiment, the MC4-R interacting moiety is notcyclic, e.g., the MC4-R interacting moiety is alkyl, unsubstitutedamino, alkylamino, dialkylamino, amidino, guanidino, etc. Examples ofalkyl MC4-R interacting moieties include straight and branched chainalkyls such as n-butyl, n-pentyl, and n-hexyl.

[0115] In another embodiment, the MC4-R interacting moiety contains oneor more nitrogen atoms, e.g., pyridinyl, pyrrolyl, pyrazinyl,imidazolyl, imidazolinyl, quinoxalinyl, or pyrimidinyl. In a furtherembodiment, the MC4-R interacting moiety is of the formula (XIII):

[0116] wherein

[0117] r is a covalent bond, CH, CH₂, CHR¹, CR¹R², or H;

[0118] t is CH, CH₂, CHR³, CR³R⁴, or H;

[0119] s is CH, CH₂, CHR⁵, CR⁵R⁶, or absent;

[0120] R is hydrogen, alkyl, alkenyl, arylalkyl, arylcarbonyl,alkoxycarbonyl, arylalkylcarbonyl, alkylcarbonyl, optionally linked toA, B, L₁, L₂, R¹, R², R³, R⁴, R⁵, or R⁶ to form one or more rings;

[0121] R¹, R², R³, R⁴, R⁵, and R⁶ are each substituted or unsubstitutedalkyl, alkenyl, alkynyl, heterocyclic, halogen, thiol, thioether,thioalkyl, hydroxyl, nitro, amino, cyano, or alkoxy, and may optionallybe linked to form a carbocyclic or heterocyclic ring. The carbocyclicring that is formed through the linkage of R, R¹, R², R³, R⁴, R⁵, or R⁶may be bridged, fused, or spiro.

[0122] In one embodiment, the MC4-R interacting moiety is represented bythe formula (XIV) below, when s is absent:

[0123] For example, in another further embodiment, the MC4-R interactingmoiety may be bicyclic, e.g., biheterocyclic, for example, quinoxalinyl.The language “linked to form a ring” refers to moieties covalentlyconnected through a chain of atoms (e.g., carbon atoms and/orheteroatoms). The chain of atoms can comprise any number of atoms, whichallow the MC4-R binding moiety to perform its intended function. In afurther embodiment, the chain of atoms is selected such that a ring withthree, four, five, six, seven, or eight members are formed. The ringthat can be formed may be spiro (e.g., connected through the same carbonatom), fused (connected through adjacent carbon atoms), or bridged(e.g., connected through carbon atoms which are neither identical noradjacent). In an embodiment, R and t are linked, e.g., to for a bicyclicmoiety. Examples of bicyclic moieties include, but are not limited to,imidazopyridinyl, pyrolloimidazolyl, cyclopentaimidazolyl,pyridopyrimidinyl, etc.

[0124] In a further embodiment R is H, alkyl, benzocarboxy,alkylcarboxy, or arylalkylcarboxy. In another further embodiment, s isCR⁵R⁶ and R⁵ and R⁶ are each methyl. In another further embodiment, r isa covalent bond, and at least one of t and s are CH₂. In another, t, r,and s are each CH₂. In another, r is a covalent bond, and t and s arelinked through a 4 carbon chain. In another further embodiment, at leastone R group is OH. In an embodiment, r is a covalent bond, t is CR³R⁴,and s is CR⁵R⁶, wherein R³, R⁴, R⁵ and R⁶ are each independentlyhydrogen or alkyl (e.g., methyl, ethyl, propyl, or butyl).

[0125] Examples of MC4-R interacting moieties include, but are notlimited to, the following structures:

[0126] In another embodiment, the invention pertains to a method fortreating an MC4-R associated state in a mammal, by administering aneffective amount of a MC4-R binding compound to a mammal, such that theMC4-R associated state is treated. Examples of MC4-R binding compoundsinclude compounds comprising the formula (II):

B-A-E  (II)

[0127] wherein:

[0128] B is a anchor moiety;

[0129] A is a cyclic moiety; and

[0130] E is a MC4-R interacting moiety, and pharmaceutically acceptablesalts thereof.

[0131] The MC4-R binding compounds of formula (II), may further compriselinking moieties, L₁ and L₂. Such MC4-R binding compounds includecompounds of the formula (III):

B-L₁-A-L₂-E  (III)

[0132] wherein B is an anchor moiety (as described above), L₁ and L₂ arelinking moieties, A is a cyclic moiety (as described above), and E is aMC4-R interacting moiety. Pharmaceutically acceptable salts of the MC4-Rbinding compound are also included.

[0133] The language “linking moiety” includes moieties which link,preferably covalently, the MC4-R interacting moiety, the cyclic moiety,and the anchor moiety of the invention. Examples of linking moietiesinclude covalent bonds, 1-10 atom chains which may be branched orunbranched, substituted or unsubstituted alkyl, heterocyclic, alkenyl,or alkynyl. The chains may be substituted with 0-3 heteroatoms or othermoieties which allow the MC4-R binding compound to perform its intendedfunction. Examples of suitable heteroatoms include sulfur, oxygen,nitrogen, and phosphorous. The invention contemplates MC4-R bindingcompounds which comprises more than two linking moieties.

[0134] In an embodiment, L₁ is a chain of 1-10 atoms (e.g., such ascarbon, nitrogen, oxygen, or sulfur atoms), e.g., 1, 2, 3, 4, 5, 6, 7,8, 9 or 10 atoms. In an embodiment, L₁ is selected from the groupconsisting of a covalent bond, C₁-C₆, C₁-C₅, C₁-C₄, C₁-C₃, C₁-C₂,branched or unbranched alkyl, wherein one, two or three of the carbonsare optionally replaced with any combination of substituted orunsubstituted oxygen, sulfur or nitrogen atoms. In a further embodiment,L₁ is a thioether (e.g., —S—CH₂—, S—CH(CH₃)—, —CH₂—S—CH₂, —S—, or—S—CH—(C₆H₅)—.), an ether (e.g., —O—CH₂ or —CH₂—O—CH₂—), a sulfoxide, asulfone, an amine (e.g., —NH—, —NH—CH₂—, —NMe—CH₂—, CH₂—NH—CH₂—, etc.)or alkyl (e.g., —CH₂—CH₂—, —CH₂—, or —CH₂—CH₂—CH₂—). In anotherembodiment, L₁ comprises a sulfonyl group. Furthermore, L₁ can besubstituted or unsubstituted (e.g., a hydrogen can be replaced byanother moiety), such that the MC4-R binding compound is capable ofperforming its intended function, e.g., bind to or interact with theMC4-R. Examples of substituents include, but are not limited to,halogens (e.g., fluorine, chlorine, bromine, iodine, etc.), alkyl (e.g.,substituted or unsubstituted, branched straight chain or cyclic, e.g.,methyl, ethyl, propyl, butyl, pentyl, etc.), alkenyl, alkynyl, hydroxyl,alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl,aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato,cyano, amino (including alkyl amino, dialkylamino, arylamino,diarylamino, and alkylarylamino), acylamino (includingalkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino,imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates,sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, azido,heterocyclyl, alkylaryl, aryl heteroaryl moieties, or combinationsthereof.

[0135] In an embodiment, examples of L₂ include a covalent bond, a chainof 1-10 atoms (e.g., such as carbon, nitrogen, oxygen, or sulfur atoms),e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 atoms. In an embodiment, L₁ isselected from the group consisting of a covalent bond, C₁-C₆, C₁-C₅,C₁-C₄, C₁-C₃, C₁-C₂, branched or unbranched alkyl, wherein one, two orthree of the carbons are optionally replaced with any combination ofsubstituted or unsubstituted oxygen, sulfur or nitrogen atoms. In afurther embodiment, L₂ is a covalent bond, —CH₂— or —NH. Furthermore, L₂may also comprise one or more carbonyl groups. For example, L₂ linkersinclude substituted urea groups (NH—C═O—NH), oxycarbonylamino groups(—O—C═O—NH), thiocarboynl groups, etc.

[0136] Furthermore, like L₁, L₂ can be substituted with any substituentsuch that the MC4-R binding compound is capable of performing itsintended function. Examples of substituents include, but are not limitedto, halogens (e.g., fluorine, chlorine, bromine, iodine, etc.), alkyl(e.g., substituted or unsubstituted, branched straight chain or cyclic,e.g., methyl, ethyl, propyl, butyl, pentyl, etc.), alkenyl, alkynyl,hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl,aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato,cyano, amino (including alkyl amino, dialkylamino, arylamino,diarylamino, and alkylarylamino), acylamino (includingalkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino,imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates,sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, azido,heterocyclyl, alkylaryl, aryl and heteroaryl moieties.

[0137] In a further embodiment, the MC4-R binding compound is of formula(III) (e.g., B-L₁-A-L₂-E), wherein B is substituted or unsubstitutedbiaryl (e.g., substituted or unsubstituted biphenyl, naphthyl,fluorenyl), unsubstituted or substituted heteroaryl (e.g., thienyl,benzothienyl, furanyl, pyrazinyl, pyrrolyl, pyrrolidinyl, etc.),unsubstituted or substituted phenyl, wherein one or more of saidsubstituents are selected from the group consisting of halogens (e.g.,bromine, fluorine, chlorine, iodine, etc.), alkyl groups (e.g.,branched, straight chain or cyclic, substituted or unsubstituted,methyl, ethyl, propyl, butyl, etc.), alkoxy groups (e.g., substituted orunsubstituted alkoxy, e.g., methoxy, ethoxy, isopropoxy, n-propoxy,isobutoxy, n-butoxy, pentoxy, cyclopentoxy, methylenedioxy,ethylenedioxy, etc.), aryl groups (e.g., substituted or unsubstitutedphenyl, heterocyclic groups), alkenyl, alkynyl, hydroxyl,alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl,aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato,cyano, thiol, thioether, thioalkyl, amino (including alkyl amino,dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,sulfates, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, andazido;

[0138] L₁ is a covalent bond, C₁-C₁₀ branched or unbranched alkyl,wherein one or more of the carbons are optionally replaced with oxygen,sulfur or nitrogen atoms;

[0139] A is a substituted or unsubstituted phenyl, heteroaryl (e.g.,pyrrolyl, pyrazinyl, thienyl, pyridinyl, etc.), bicyclic (e.g.,methylenedioxyphenyl, isoindole, indole, and indan )or biaryl (e.g.,naphthyl, quinoxalinyl, purinyl, etc.) wherein said substituent isselected from the group consisting of halogens (e.g., bromine, fluorine,chlorine, iodine, etc.), alkyl groups (e.g., branched, straight chain orcyclic, substituted or unsubstituted, methyl, ethyl, propyl, butyl,etc.), alkoxy groups (e.g., substituted or unsubstituted alkoxy, e.g.,methoxy, ethoxy, isopropoxy, n-propoxy, isobutoxy, n-butoxy, pentoxy,cyclopentoxy, methylenedioxy, ethylenedioxy, etc.), aryl groups (e.g.,substituted or unsubstituted phenyl, heterocyclic groups), alkenyl,alkynyl, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl,aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato,cyano, amino (including alkyl amino, dialkylamino, arylamino,diarylamino, and alkylarylamino), acylamino (includingalkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino,imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates,sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, and azido;

[0140] L₂ is a covalent bond, a chain of 1-10 atoms (e.g., such ascarbon, nitrogen, oxygen, or sulfur atoms), e.g., 1, 2, 3, 4, 5, 6, 7,8, 9 or 10 atoms. In an embodiment, L₁ is selected from the groupconsisting of a covalent bond, C₁-C₆, C₁-C₅, C₁-C₄, C₁-C₃, C₁-C₂,branched or unbranched alkyl, wherein one, two or three of the carbonsare optionally replaced with oxygen, sulfur or nitrogen atoms,substituted or unsubstituted amino (e.g., —NH—, —NH—CH₂), ether,thioether, or alkyl (e.g., C₁-C₁₀, —CH₂—, —CH₂—CH₂—, or —CH₂—CH₂—CH₂—,etc.);

[0141] E is unsubstituted amino, unsubstituted and substitutedalkylamino (e.g., 3-aminopropylamino), dialkylamino (e.g., dimethylamino, diethyl amino), amidino, guanidino, heterocyclic (e.g.,substituted and unsubstituted imidazolyl, imidazolinyl, piprazinyl,morpholinyl, piperidinyl, imidoazopyridinyl, pyrolloimidazolyl,pyridinyl, or pyrimidinyl) moieties, aryl (e.g., phenyl, heteroaromatic,e.g., substituted and unsubstituted pyrazinyl, imidazolyl, quinoxalinyl,or pyrimidinyl), wherein said substituents include, but are not limitedto, amino (e.g., unsubstituted amino, alkylamino, dialkyl amino),aminoalkyl (e.g., methylamino, ethylamino, propylamino, etc.), alkyl(e.g., branched and straight chain, substituted and unsubstituted (e.g.,carboxy, hydroxy, halogen, amino, cyano, nitro, etc. substituted),methyl, ethyl, propyl, butyl, etc.), aryl (e.g., phenyl,heteroaromatic), alkenyl (e.g., branched or straight chain, substitutedor unsubstituted), alkynyl, etc, and pharmaceutically acceptable saltsthereof.

[0142] In another embodiment, the invention pertains to a method fortreating an MC4-R associated state in a mammal by administering aneffective amount of a MC4-R binding compound to a mammal, such that theMC4-R associated state is treated. In an embodiment, the compound is ofthe formula (IV):

[0143] wherein

[0144] A is a substituted or unsubstituted phenyl, heteroaryl (e.g.,pyrrolyl, pyrazinyl, pyridinyl, etc.), or biaryl (e.g., naphthyl,quinoxalinyl, purinyl, etc.) wherein said substituent is selected fromthe group consisting of halogens (e.g., bromine, fluorine, chlorine,iodine, etc.), alkyl groups (e.g., branched, straight chain or cyclic,substituted or unsubstituted, methyl, ethyl, propyl, butyl, etc.),alkoxy groups (e.g., substituted or unsubstituted alkoxy, e.g., methoxy,ethoxy, isopropoxy, n-propoxy, isobutoxy, n-butoxy, pentoxy,cyclopentoxy, methylenedioxy, ethylenedioxy, etc.), aryl groups (e.g.,substituted or unsubstituted phenyl, heterocyclic groups), alkenyl,alkynyl, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl,aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato,cyano, amino (including alkyl amino, dialkylamino, arylamino,diarylamino, and alkylarylamino), acylamino (includingalkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino,imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates,sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, and azido;

[0145] B is substituted or unsubstituted biaryl (e.g., substituted orunsubstituted biphenyl, naphthyl, fluorenyl), unsubstituted orsubstituted heteroaryl (e.g., thienyl, benzothienyl, furanyl, pyrazinyl,pyrrolyl, pyrrolidinyl, etc.), unsubstituted or substituted phenyl,wherein one or more of said substituents are selected from the groupconsisting of halogens (e.g., bromine, fluorine, chlorine, iodine,etc.), alkyl groups (e.g., branched, straight chain or cyclic,substituted or unsubstituted, methyl, ethyl, propyl, butyl, etc.),alkoxy groups (e.g., substituted or unsubstituted alkoxy, e.g., methoxy,ethoxy, isopropoxy, n-propoxy, isobutoxy, n-butoxy, pentoxy,cyclopentoxy, methylenedioxy, ethylenedioxy, etc.), aryl groups (e.g.,substituted or unsubstituted phenyl, heterocyclic groups), alkenyl,alkynyl, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl,aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato,cyano, amino (including alkyl amino, dialkylamino, thiol, thioether,thioalkyl, arylamino, diarylamino, and alkylarylamino), acylamino(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,sulfates, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, andazido;

[0146] L₁ and L₂ are selected from the group consisting of a covalentbond, C₁-C₄ branched or unbranched, substituted or unsubstituted alkyl,wherein one or two of the carbons are optionally replaced with oxygen,sulfur or nitrogen atoms;

[0147] r is a covalent bond, CH, CH₂, CHR¹, CR¹R², or H;

[0148] t is CH, CH₂, CHR³, CR³R⁴, or H;

[0149] s is CHR₅, CR₅R₆ or absent (e.g., leaving a non-cyclic diamine);

[0150] R is H, substituted or unsubstituted alkyl, arylalkyl, orheteroalkyl, and may optionally be linked to A, B, L₁, or L₂;

[0151] R¹, R², R³, R⁴, R⁵, and R⁶ are each substituted or unsubstitutedalkyl, halogen, thiol, thioether, thioalkyl, alkoxy, and may beoptionally linked to each other to form additional ring moieties, e.g.,quinoxalinyl. Pharmaceutically acceptable salts of the MC4-R bindingcompounds are also included.

[0152] In one further embodiment, A is substituted or unsubstitutedphenyl. Examples of substituents include halogens (e.g., fluorine,chlorine, iodine, bromine), alkoxy, alkyl (e.g., methyl,trifluoromethyl), and amino moieties. In other embodiments, A isheteroaromatic, (e.g., thienyl), or biaryl, (e.g., napthyl orquinoxalinyl).

[0153] The invention also pertains to methods for treating an MC4-Rassociated state in a mammal comprising by administering an effectiveamount of a MC4-R binding compound of the formula (V):

[0154] B is substituted or unsubstituted biaryl, unsubstituted orsubstituted heterocyclic, or unsubstituted or substituted phenyl,wherein one or more of said substituents are halogens, alkyl alkynyl,alkoxy, aryl, amino, thiol, thioether, thioalkyl, cyano, or nitro;

[0155] L₁ is a covalent bond, C₁-C₁₀ branched or unbranched alkyl,wherein one or two of the carbons are optionally replaced with oxygen,sulfur or nitrogen atoms;

[0156] L₂ is a covalent bond, substituted or unsubstituted amino, ether,thioether, or alkyl;

[0157] E is substituted or unsubstituted alkyl, amino, amidino,guanidino, heterocyclic, or aryl, wherein said substituents are amino,arylalkyl, aminoalkyl, alkyl, aryl, alkenyl, or alkynyl;

[0158] Π is a covalent bond, a carbon atom, a nitrogen atom,heterocyclic, alkyl, carbocyclic, or aryl;

[0159] L₃ is a covalent bond, C₁-C₆ branched, unbranched or cyclic alkyl(wherein one, two or three of the carbons are optionally replaced withoxygen, sulfur or nitrogen atoms), carbonyl, aminocarbonyl,aminocarbonylamino, aminocarbonyloxy, or an aminothiocarbonyl moiety;and

[0160] Λ is substituted or unsubstituted heterocyclic, aryl, alkoxy,amino, alkyl, alkenyl, alkynyl, or hydrogen; and

[0161] λ is 0, 1 or 2, and pharmaceutically acceptable salts thereof.

[0162] Examples of MC4-R binding compounds with this structure include,but are not limited to, compounds, wherein Π is a carbon atom, L₃ isaminocarbonyloxy, Λ is substituted aryl, λ is one, L₁ and L₂ are eachCH₂, and B and E are each pipridinyl. Examples of substituents for Λinclude but are not limited to, alkoxy (e.g., C₁-C₁₀ alkoxy, e.g.,methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy,nonoxy, and decoxy), cyano, halogens (e.g., fluorine, chlorine, bromine,iodine), alkyl (e.g., straight or branched chain, etc.), aryl, alkenyl,alkynyl, nitro, amino, or any other substituents which enables the MC4-Rbinding compound to perform its intended function, e.g., treat an MC4-Rassociated state.

[0163] Other examples of compounds of formula (V) include, but are notlimited to, compounds wherein Π, L₂ and L₃ together are a singlecovalent bond, E is alkyl, and B is substituted or unsubstitutedheterocyclic. In other compounds of formula (V), Π is a nitrogen atom,L₂, L₁ and L₃ are each alkyl, E is substituted amino (e.g., alkylsubstituted), or heterocyclic (e.g., piprazinyl, piperidinyl,morpholinyl, etc.) and B and Λ are each aryl (e.g., phenyl, anthracenyl,biaryl, e.g., naphthyl).

[0164] In another further embodiment, the invention pertains to yetanother method for treating an MC4-R associated state in a mammal byadministering to a mammal an effective amount of a MC4-R bindingcompound of the formula(VI):

[0165] wherein

[0166] P¹, P², P³, and P⁴ are optionally substituted carbon, sulfur, ornitrogen, and wherein one of P¹, P², P³, and P⁴ may represent a covalentbond;

[0167] Z¹, Z², Z³, Z⁴, and Z⁵ are optionally substituted carbon ornitrogen;

[0168] L¹ is a covalent bond, C₁-C₆ branched or unbranched alkyl,wherein one or two of the carbons are optionally replaced with oxygen,sulfur or nitrogen atoms;

[0169] L₂ is a covalent bond, substituted or unsubstituted amino, ether,thioether, or alkyl;

[0170] J is an unsubstituted or substituted nitrogen containingheterocycle or a substituted or unsubstituted amino group, andpharmaceutically acceptable salts thereof.

[0171] Examples of substituents of P¹, P², P³, P⁴, Z¹, Z², Z³, Z⁴, andZ⁵ include halogens (e.g., bromine, fluorine, chlorine, iodine, etc.),alkyl groups (e.g., branched, straight chain or cyclic, substituted orunsubstituted, methyl, ethyl, propyl, butyl, etc.), alkoxy groups (e.g.,substituted or unsubstituted alkoxy, e.g., methoxy, ethoxy, isopropoxy,n-propoxy, isobutoxy, n-butoxy, pentoxy, cyclopentoxy, methylenedioxy,ethylenedioxy, etc.), aryl groups (e.g., substituted or unsubstitutedphenyl, heterocyclic groups), alkenyl, alkynyl, hydroxyl,alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl,aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato,cyano, amino (including alkyl amino, dialkylamino, arylamino,diarylamino, and alkylarylamino), acylamino (includingalkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino,imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates,sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, and azidogroups.

[0172] In a further embodiment, P¹, P², P³, and P⁴ are each substitutedor unsubstituted carbon (e.g., CH). For example, P¹ and P³ may be CH. Inanother further embodiment, P² and P⁴ are each CH, CF, CCl, CBr, CI,C-aryl, C-alkyl (e.g., C—Me, C-ethyl, C-propyl, etc.) C-alkoxy (e.g.,C—OMe, C—O-ethyl, C—OCF₃, etc.). In a further embodiment, P² is CH andP⁴ is CCl or CF. In an embodiment, P¹ is a covalent bond, P² and P³ areeach optionally substituted carbon, and P⁴ is S (e.g., thienyl).

[0173] In a third further embodiment, Z³ and Z⁴ are each CH.

[0174] In a fourth further embodiment, Z¹ is CH, or covalently linked toZ² to form a naphthyl ring. Examples of Z² include CH, C—(C≡CH), CCl,CBr, CI, and CF. Furthermore, Z² may be substituted with a chain ofatoms which covalently links it to Z¹ to form a naphthyl ring.

[0175] Examples of Z⁵ include, but are not limited to, CH and C-alkoxy.The term “C-alkoxy” includes carbon atoms covalently bound to an alkoxygroup, as described below. Examples of alkoxy groups include methoxy,ethoxy, propoxy, butoxy, etc.

[0176] In yet another further embodiment, L₂ is a covalent bond.

[0177] Examples of J include, but are not limited to, substituted orunsubstituted piprazinyl, imidoazopyridinyl, pyrolloimidazolyl,pyrrolyl, azetidinyl, azapanyl, diazapanyl, pyrimidinyl, pyridinyl,morpholinyl, or piperidinyl. Furthermore, J may be a substituted orunsubstituted fused ring or bridged heterocycle.

[0178] In a further embodiment, each of P¹, P², P³, and P⁴ are eachoptionally substituted carbon; Z¹, Z², Z³, Z⁴, and Z⁵ are each alsooptionally substituted carbon (e.g., alkoxy substituted, halogensubstituted or linked to form a ring); wherein L₁ is either —S—CH₂—, orCH₂—CH₂. In a further embodiment, L₂ is a covalent bond and J is amoiety of formula XIII, as described above.

[0179] In another embodiment, the MC4-R binding compound is of formula(VII):

[0180] wherein

[0181] Z¹, Z², Z³, Z⁴, and Z⁵ are CH, N, or substituted carbon; and

[0182] P¹, P², P³, P⁴, and P⁵ are CH, N or substituted carbon.

[0183] Examples of substituents of Z¹, Z², Z³, Z⁴, Z⁵, P¹, P², P³, P⁴,and P⁵ include halogens (e.g., bromine, fluorine, chlorine, iodine,etc.), alkyl groups (e.g., branched, straight chain or cyclic,substituted or unsubstituted, methyl, ethyl, propyl, butyl, etc.),alkoxy groups (e.g., substituted or unsubstituted alkoxy, e.g., methoxy,ethoxy, isopropoxy, n-propoxy, isobutoxy, n-butoxy, pentoxy,cyclopentoxy, methylenedioxy, ethylenedioxy, etc.), aryl groups (e.g.,substituted or unsubstituted phenyl, heterocyclic groups), alkenyl,alkynyl, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl,aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato,cyano, amino (including alkyl amino, dialkylamino, arylamino,diarylamino, and alkylarylamino), acylamino (includingalkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino,imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates,sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, and azidogroups.

[0184] In a further embodiment, P¹, P², P³, P⁴ and P⁵ are eachsubstituted or unsubstituted carbon (e.g., CH). For example, P¹ and P³may be CH. In another further embodiment, P² and P⁴ are each CH, CF,CCl, CBr, or CI. Furthermore, P¹, P², P³, and P⁴ can be linkedcovalently to form a bicyclic ring.

[0185] In a third further embodiment, Z³ and Z⁴ are each CH.

[0186] In a fourth further embodiment, Z¹ is CH, or covalently linked toZ² to form a naphthyl ring. Examples of Z² include CH, C—(C≡CH), CCl,CBr, CI, and CF. Furthermore, Z² may be substituted with a chain ofatoms which covalently links it to Z¹ to form a naphthyl ring.

[0187] In a further embodiment, P⁵ is C—L₂—J, wherein C is a carbonatom, L₂ is a linking moiety, e.g., a covalent bond, substituted orunsubstituted amino, ether, thioether, or alkyl; and J is anunsubstituted or substituted nitrogen containing heterocycle or asubstituted or unsubstituted amino group. In yet a further embodiment,L₂ is a covalent bond and J is a moiety of formula (XIII):

[0188] wherein

[0189] r is a covalent bond, CH, CH₂, CHR¹, CR¹R², or H;

[0190] t is CH, CH₂, CHR³, CR³R⁴, or H;

[0191] s is CH, CH₂, CHR⁵, CR⁵R⁶, or absent;

[0192] R is hydrogen, alkyl, alkenyl, arylalkyl, arylcarbonyl,alkoxycarbonyl, arylalkylcarbonyl, alkylcarbonyl, optionally linked toA, B, L₁, L₂, R¹, R², R³, R⁴, R⁵, or R⁶ to form one or more rings;

[0193] R¹, R², R³, R⁴, R⁵, and R⁶ are each halogen, thiol, thioether,thioalkyl, alkoxy, alkyl, alkenyl, alkynyl, heterocyclic, hydroxyl,nitro, amino, cyano, aryl, optionally linked to form a ring with R, R¹,R², R³, R⁴, R⁵, or R⁶.

[0194] In a further embodiment, compounds of formula VII also includecompounds wherein J is

[0195] wherein R is alkyl (e.g., methyl, ethyl, propyl, butyl, etc.) orhydrogen. In another embodiment, the compounds include those in whichP¹, P², and P³ are each CH, and P⁴ is CCl. Furthermore, the compoundsalso include those wherein Z¹, Z³, and Z⁴ are each CH, Z⁵ is COMe, andZ² is CBr, as well as those wherein Z¹ is covalently linked to Z² toform a naphthyl ring, and Z³, Z⁴ and Z⁵ are each CH.

[0196] In another embodiment, the MC4-R binding compound is of formula(VIII):

[0197] wherein

[0198] Z¹, Z², Z³, Z⁴, and Z⁵ are CH, N, or substituted carbon; and

[0199] P¹, P², P³, P⁴, and P⁵ are CH, N or substituted carbon.

[0200] Examples of substituents of Z¹, Z², Z³, Z⁴, Z⁵, P¹, P², P³, P⁴,and P⁵ include halogens (e.g., bromine, fluorine, chlorine, iodine,etc.), alkyl groups (e.g., branched, straight chain or cyclic,substituted or unsubstituted, methyl, ethyl, propyl, butyl, etc.),alkoxy groups (e.g., substituted or unsubstituted alkoxy, e.g., methoxy,ethoxy, isopropoxy, n-propoxy, isobutoxy, n-butoxy, pentoxy,cyclopentoxy, methylenedioxy, ethylenedioxy, etc.), aryl groups (e.g.,substituted or unsubstituted phenyl, heterocyclic groups), alkenyl,alkynyl, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl,aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato,cyano, amino (including alkyl amino, dialkylamino, arylamino,diarylamino, and alkylarylamino), acylamino (includingalkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino,imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates,sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, and azidogroups.

[0201] In a further embodiment, P¹, P², P³, and P⁴ are each substitutedor unsubstituted carbon (e.g., CH). For example, P¹ and P³ may be CH. Inanother further embodiment, P² and P⁴ are each CH, CF, CCl, CBr, or CI.Furthermore, P¹, P², P³, and P⁴ can be linked covalently to form abicyclic ring.

[0202] In a third further embodiment, Z³ and Z⁴ are each CH.

[0203] In a fourth further embodiment, Z¹ is CH, or covalently linked toZ² to form a naphthyl ring. Examples of Z² include CH, C—(C≡CH), CCl,CBr, CI, and CF. Furthermore, Z² may be substituted with a chain ofatoms which covalently links it to Z, to form a naphthyl ring.

[0204] In a further embodiment, P⁵ is C—L₂—J, wherein C is a carbonatom, L₂ is a linking moiety, e.g., a covalent bond, substituted orunsubstituted amino, ether, thioether, or alkyl; and J is anunsubstituted or substituted nitrogen containing heterocycle or asubstituted or unsubstituted amino group. In yet a further embodiment,L₂ is a covalent bond and J is a moiety of formula (XIII):

[0205] wherein

[0206] r is a covalent bond, CH, CH₂, CHR¹, CR¹R², or H;

[0207] t is CH, CH₂, CHR³, CR³R⁴, or H;

[0208] s is CH, CH₂, CHR⁵, CR⁵R⁶, or absent;

[0209] R is hydrogen, alkyl, alkenyl, arylalkyl, arylcarbonyl,alkoxycarbonyl, arylalkylcarbonyl, alkylcarbonyl, optionally linked toA, B, L₁, L₂, R¹, R², R³, R⁴, R⁵, or R⁶ to form one or more rings;

[0210] R¹, R², R³, R⁴, R⁵, and R⁶ are each halogen, thiol, thioether,thioalkyl, alkoxy, alkyl, alkenyl, alkynyl, heterocyclic, aryl,hydroxyl, nitro, amino, cyano, optionally linked to form a ring with R,R¹, R², R³, R⁴, R⁵, or R⁶.

[0211] In another embodiment, the invention pertains to MC4-R bindingcompounds of formulae VII and VIII. Examples of MC4-R binding compoundof these formulae include, for example, compounds wherein P⁵ is a carboncovalently bonded to a moiety of formula XIII. In a further embodiment,the moiety of formula XIII is not benzoimidazole. In another furtherembodiment, Z³ is not ethoxy. In another embodiment, the inventionpertains to both methods of using and MC4-R binding compounds of formula(IX):

[0212] wherein:

[0213] P² is CH, CF, CCl, CBr, C-alkyl, C-aryl, C-alkoxy, C—CN, C—OH,Cl, or a covalent bond;

[0214] P³ is CH, CF, CCl, CBr, C-alkyl, C-aryl, C-alkoxy, C—CN, C—OH, orCI;

[0215] P⁴ is CH, CCl, CBr, CF, C-alkyl, C-aryl, C-alkoxy, C—CN, C—OH, orCI;

[0216] G¹ and G² are each independently CH₂, S, or O;

[0217] r is a covalent bond or CH₂;

[0218] t is CH₂, CHR³, or CR³R⁴;

[0219] s is CH₂, CHR⁵ or CR⁵R⁶;

[0220] R is hydrogen alkyl, alkoxycarbonyl, or alkylcarbonyl;

[0221] Z¹ is CH, or covalently linked to Z² to form a naphthyl ring;

[0222] Z² is CH, C—(C≡CH), CCl, CBr, CI, CF, or covalently linked to Z¹to form a naphthyl ring;

[0223] Z⁵ is CH, C-alkoxy (e.g., C—OMe);

[0224] R³, R⁴, R⁵, and R⁶ are methyl, ethyl, hydroxyl, alkoxy, halogen,cyano, nitro, amino, or pharmaceutically acceptable salts thereof.

[0225] The language “linked to form a naphthyl ring” includes moietieswhich join Z¹ and Z² to form a naphthyl (fused) ring system. Examples ofsuch Z¹ and Z² groups include, but are not limited to, —CH═CH—CH═CH—.

[0226] In a further embodiment, Z¹ is CH; Z² is CBr; and Z⁵ is C—OMe.

[0227] In another further embodiment, P² is CH. In another, P⁴ is CCl orCF. G¹ and G² are each CH₂. In another, G¹ and G² together are—CH₂—CH₂—, —CH₂O—, —O—CH₂—, —CH₂—S— or —S—CH₂—. In another, Z¹ and Z²are linked to form a naphthyl ring.

[0228] In an embodiment, r is a covalent bond, s is CR⁵R⁶, and t isCR³R⁴,wherein R³, R⁴, R⁵, and R⁶ are each independently hydrogen oralkyl (e.g., methyl, ethyl, propyl, or butyl). In another embodiment, Ris hydrogen or alkyl (e.g., methyl, ethyl, propyl or butyl, etc.)

[0229] The invention pertains to MC4-R binding compound of the formula(VII):

[0230] wherein

[0231] Z¹, Z², Z³, Z⁴, and Z⁵ are CH, N, or substituted carbon; and

[0232] P¹, P², P³, P⁴, and P⁵ are CH, N or substituted carbon.

[0233] P⁵ is C—L₂—J, wherein L₂ is a covalent bond, alkyl (e.g., C₁-C₃),amino, ether, carbonyl, etc., and wherein J is a moiety of the formula(XIII):

[0234] wherein

[0235] r is a covalent bond, CH, CH₂, CHR¹, CR¹R², or hydrogen toprovide an acyclic group;

[0236] t is CH, CH₂, CHR³, CR³R⁴, or hydrogen to provide an acyclicgroup;

[0237] s is CH, CH₂, CHR⁵, CR⁵R⁶, or absent;

[0238] R is hydrogen, alkyl, alkenyl, arylalkyl, arylcarbonyl,alkoxycarbonyl, arylalkylcarbonyl, alkylcarbonyl, optionally linked toR¹, R², R³, R⁴, R⁵, or R⁶ to form one or more rings; and

[0239] R¹, R², R³, R⁴, R⁵, and R⁶ are each halogen, thiol, thioether,thioalkyl, alkoxy, alkyl, alkenyl, alkynyl, heterocyclic, hydroxyl,nitro, amino, cyano, aryl, optionally linked to form a ring with R, R¹,R², R³, R⁴, R⁵, or R⁶.

[0240] The invention also pertains to MC4-R binding compound of theformula (VIII):

[0241] wherein

[0242] Z¹, Z², Z³, Z⁴, and Z⁵ are CH, N, or substituted carbon;

[0243] P¹, P², P³, and P⁴ are CH, N or substituted carbon; and

[0244] P⁵ is C—L₂—J, wherein L₂ is a covalent bond, alkyl (e.g., C₁-C₃),amino, ether, carbonyl, etc., and wherein J is a moiety of the formula(XIII):

[0245] wherein

[0246] r is a covalent bond, CH, CH₂, CHR¹, CR¹R², or hydrogen toprovide an acyclic group;

[0247] t is CH, CH₂, CHR³, CR³R⁴, or hydrogen to provide an acyclicgroup;

[0248] s is CH, CH₂, CHR⁵, CR⁵R⁶, or absent;

[0249] R is hydrogen, alkyl, alkenyl, arylalkyl, arylcarbonyl,alkoxycarbonyl, arylalkylcarbonyl, alkylcarbonyl, optionally linked toR¹, R², R³, R⁴, R⁵, or R⁶ to form one or more rings; and

[0250] R¹, R², R³, R⁴, R⁵, and R⁶ are each halogen, thiol, thioalkyl,thioether, alkoxy, alkyl, alkenyl, alkynyl, heterocyclic, hydroxyl,nitro, amino, cyano, aryl, optionally linked to form a ring with R, R¹,R², R³, R⁴, R⁵, or R⁶.

[0251] The invention also pertains to MC4-R binding compound of theformula (XV):

[0252] wherein

[0253] Z¹, Z², Z³, Z⁴, and Z⁵ are CH, N, or substituted carbon;

[0254] P¹, P², P³, and P⁴ are CH, N or substituted carbon; and

[0255] P⁵ is C—L₂—J, wherein L₂ is a covalent bond, alkyl (e.g., C₁-C₃),amino, ether, carbonyl, etc., and wherein J is a moiety of the formula(XIII):

[0256] wherein

[0257] r is a covalent bond, CH, CH₂, CHR¹, CR¹R², or hydrogen toprovide an acyclic group;

[0258] t is CH, CH₂, CHR³, CR³R⁴, or hydrogen to provide an acyclicgroup;

[0259] s is CH, CH₂, CHR⁵, CR⁵R⁶, or absent;

[0260] R is hydrogen, alkyl, alkenyl, arylalkyl, arylcarbonyl,alkoxycarbonyl, arylalkylcarbonyl, alkylcarbonyl, optionally linked toR¹, R², R³, R⁴, R⁵, or R⁶ to form one or more rings; and

[0261] R¹, R², R³, R⁴, R⁵, and R⁶ are each halogen, thiol, thioalkyl,thioether, alkoxy, alkyl, alkenyl, alkynyl, heterocyclic, hydroxyl,nitro, amino, cyano, aryl, optionally linked to form a ring with R, R¹,R², R³, R⁴, R⁵, or R⁶.

[0262] The invention also pertains to MC4-R binding compound of theformula (XVI):

[0263] wherein

[0264] Z¹, Z², Z³, Z⁴, and Z⁵ are CH, N, or substituted carbon;

[0265] P¹, P², P³, and P⁴ are CH, N or substituted carbon; and

[0266] P⁵ is C—L₂—J, wherein L₂ is a covalent bond, alkyl (e.g., C₁-C₃),amino, ether, carbonyl, etc., and wherein J is a moiety of the formula(XIII):

[0267] wherein

[0268] r is a covalent bond, CH, CH₂, CHR¹, CR¹R², or hydrogen toprovide an acyclic group;

[0269] t is CH, CH₂, CHR³, CR³R⁴, or hydrogen to provide an acyclicgroup;

[0270] s is CH, CH₂, CHR⁵, CR⁵R⁶, or absent;

[0271] R is hydrogen, alkyl, alkenyl, arylalkyl, arylcarbonyl,alkoxycarbonyl, arylalkylcarbonyl, alkylcarbonyl, optionally linked toR¹, R², R³, R⁴, R⁵, or R⁶ to form one or more rings; and

[0272] R¹, R², R³, R⁴, R⁵, and R⁶ are each halogen, thiol, thioalkyl,thioether, alkoxy, alkyl, alkenyl, alkynyl, heterocyclic, hydroxyl,nitro, amino, cyano, aryl, optionally linked to form a ring with R, R¹,R², R³, R⁴, R⁵, or R⁶.

[0273] In a further embodiment, the invention includes compounds whereinP¹, P², P³, and P⁴ of any one of formulas VII, VIII, XV, or XVI are eachsubstituted or unsubstituted carbon. For example, in one embodiment, P¹is CH. In another example, at least one of P², P³ and P⁴ is asubstituted carbon. In a further embodiment, P², P³ and P⁴ are selectedfrom the group consisting of CH, CF, Cl, CBr, C-alkyl, C-alkoxy, or CI.

[0274] In another embodiment, the compounds of formulae VII, VIII, XV,or XVI, include compounds wherein Z³ and Z⁴ are each CH. In anotherfurther embodiment of the formulae, Z¹ is CH. For example, in anotherfurther embodiment, Z¹ is covalently linked to Z² to form a naphthylring. Z² is CH, C—(C≡CH), CCl, CBr, CI, and CF.

[0275] In another further embodiment, the compounds of the inventioninclude compounds of formulae VII, VIII, XV, or XVI, wherein L₂ is acovalent bond. Also included are compounds wherein R is H, alkyl,benzocarboxy, alkylcarboxy, or arylalkylcarboxy.

[0276] In another further embodiment, the compounds of the inventioninclude compounds of formulae VII, VIII, XV, or XVI, wherein s is CR⁵R⁶and R⁵ and R⁶ are each methyl. In another example r is a covalent bond.Alternatively, each of t, r and s may be CH₂.

[0277] Another embodiment of the invention pertains to compounds of theformula XVII:

[0278] wherein:

[0279] P¹, P², P³, and P⁴ are each selected from a substituted orunsubstituted carbon, wherein one of P¹-P⁴ is optionally replaced by anitrogen atom, or the ring bearing P¹-P⁴ is a thiophene ring, whereinP³-P⁴ together are replaced by a sulfur atom;

[0280] Z¹ is CH or a carbon substituted with R⁷;

[0281] Z² is CH or a carbon substituted with R⁸;

[0282] Z³, Z⁴ and Z⁵ are each independently selected from CH or a carbonsubstituted with R⁹;

[0283] R⁷ is C₁₋₃ alkoxy, C₁₋₃ haloalkoxy, cyano, C₁₋₃ cyanoalkyl, halo,C₁₋₃ alkyl, or C₁₋₃ haloalkyl;

[0284] R⁸ is halo, C₁₋₃ alkyl, C₁₋₃ haloalkyl, or R⁷ and R⁸ are takentogether with their intervening atoms to form a fused, 5-6 memberedaromatic or nonaromatic, ring having 0-2 ring heteroatoms selected fromoxygen, nitrogen or sulfur;

[0285] each R⁹ is independently selected from halo, cyano,trialkylsiloxy, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, C₁₋₆ alkenyl, C₁₋₆ alkynyl, N(R¹⁰)₂, (C₁₋₆ alkyl)-N(R¹⁰)₂,O(C₁₋₆ alkyl)-N(R¹⁰)₂, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylthio, or phenyl, ortwo R⁹ on neighboring carbons are taken together to form a fused, 5-6membered aromatic or nonaromatic ring having 0-2 ring heteroatomsselected from oxygen, nitrogen, or sulfur;

[0286] each R¹⁰ is independently selected from hydrogen, C₁₋₄ alkyl, ortwo R¹⁰ on the same nitrogen are taken together with their interveningnitrogen to form a 5-6 membered ring having 1-2 ring heteroatomsselected from oxygen, nitrogen or sulfur;

[0287] L₂ is a covalent bond, a substituted or unsubstituted 1-2 carbonchain or a 2 carbon carbonyl chain, wherein one of the carbons alongwith the hydrogen attached thereto is optionally replaced by oxygen,N(R¹⁰), or sulfur;

[0288] t is CH₂, CHR³, or CR³R⁴, and s is CH₂, CHR⁵, or CR⁵R⁶, or t-staken together is CH═CH, CR³═CH, CH═CR⁵ or CR³═CR⁵;

[0289] R³, R⁴, R⁵, and R⁶ are each independently selected from C₁₋₄alkyl, C₁₋₄ alkylcarboxyl, C₁₋₄ alkoxycarbonyl, C₁₋₄ alkylcarboxamide,or two of R³, R⁴, R⁵, and R⁶ are taken together with their interveningatom or atoms to form a fused 3-7 membered aromatic or non-aromatic ringor 3-7 membered spirocyclic ring, having 0-2 ring heteroatoms selectedfrom oxygen, nitrogen or sulfur;

[0290] R is hydrogen or a C₁₋₈ alkyl or C₁₋₈ alkylcarbonyl that issubstituted with 0-2 R¹¹, or R and R⁵ are taken together with theirintervening atoms to form a fused pyrrolidino or piperidino ring, or Rand L₂ are taken together with their intervening atoms to form a fusedfive membered ring having 1-2 ring heteroatoms selected from oxygen,nitrogen or sulfur;

[0291] each R¹¹ is independently selected from C₁₋₃ alkyl, cyano, halo,haloalkyl, N(R¹⁰)₂, (C═O)N(R¹⁰)₂, OC(═O)N(R¹⁰)₂, OH, S(C₁₋₆ alkyl),SO₂(C₁₋₆ alkyl), SO₂N(R¹⁰)₂, C₁₋₆ alkoxy, C₁₋₆ alkylcarbonyl, C₁₋₆alkylcarboxyl, C₁₋₆ alkoxycarboxyl, C₅₋₆ aryl, C₆₋₁₀ arylalkyl, or a 3-6membered heterocyclyl having 1 or 2 heteroatoms selected from oxygen,nitrogen or sulfur; or a pharmaceutically acceptable salt thereof.

[0292] In certain embodiments, where carbon chains or R groups (e.g, L₂,R, R³, R⁴, R⁵, R⁶, etc.) contain an alkyl or an aryl, they may besubstituted or unsubstituted with one or more substituents. In certainembodiments where R groups are taken together to form a ring (e.g., R⁷and R⁸ are taken together to form a ring), the resulting ring may besubstituted or unsubstituted. Examples of substituents (e.g., of P¹, P²,P³, P⁴, P⁵, Z³, Z⁴, Z⁵, R, R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹)include halogens (e.g., bromine, fluorine, chlorine, iodine, etc.),oxygen, sulfur, alkyl groups (e.g., branched, straight chain or cyclic,substituted or unsubstituted, methyl, ethyl, propyl, butyl, etc.),alkoxy groups (e.g., substituted or unsubstituted alkoxy, e.g., methoxy,ethoxy, isopropoxy, n-propoxy, isobutoxy, n-butoxy, pentoxy,cyclopentoxy, methylenedioxy, ethylenedioxy, etc.), aryl groups (e.g.,substituted or unsubstituted phenyl, heterocyclic groups), alkenyl,alkynyl, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl,aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato,cyano, amino (including alkyl amino, dialkylamino, arylamino,diarylamino, and alkylarylamino), acylamino (includingalkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino,imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates,sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, and azidogroups.

[0293] In certain embodiments, P¹, P², P³ and P⁴ are each independentlyselected from a substituted (e.g, CF) or unsubstituted (e.g., CH)carbon. For example, P¹ P² and P³ can be CH. Specific examples of P² andP⁴ independently include CH, CF, CCl, CBr, or CI.

[0294] In a further embodiment, the compound of formula (XVII) has oneor more features selected from:

[0295] (a) Z¹ is a carbon substituted with R⁷;

[0296] (b) Z², Z³ and Z⁵ are each CH;

[0297] (c) Z⁴ is a carbon substituted with R⁹;

[0298] (d) L² is a covalent bond;

[0299] (e) t is CH₂;

[0300] (f) s is CH₂; and

[0301] (g) R is hydrogen or C₁₋₈ alkyl that is substituted with 0-2 R¹¹.

[0302] In one embodiment, the compound has all of the above features(a)-(g), and P¹, P², P³ and P⁴ are each independently selected from asubstituted (e.g, CF) or unsubstituted (e.g., CH) carbon. In one aspect,R is hydrogen. In another aspect, R⁷ is alkoxy. In another aspect, R⁹ ishalo cyano or alkynyl. Specific examples of R⁹ include F, Br, or Cl.

[0303] In yet another aspect, the compound of Formula (XVII) has one ormore (a)-(g); and further include one or more of the specific features(h)-(k):

[0304] (h) P¹, P², and P³ are each an unsubstituted carbon, and P⁴ is anunsubstituted carbon, or a carbon substituted with a halogen or alkoxy;

[0305] (i) R⁷ is alkoxy;

[0306] (j) R⁹ is a halo, cyano or alkynyl; and

[0307] (k) R is hydrogen, or C₁₋₄ alkyl that is substituted with 0-2R¹¹, wherein R¹¹ can be C₁₋₃ alkyl, cyano, halo, C₁₋₄ alkoxy, or a 5-6membered heterocyclyl having 1 or 2 heteroatoms selected from oxygen,nitrogen or sulfur.

[0308] In one aspect the compound has all of the above features (h)-(k).In another aspect, P¹, P², and P³ are each an unsubstituted carbon; P⁴is CH, CF, or Cl. In yet a further aspect, R⁷ is alkoxy. In anotheraspect R is C₁₋₄ alkyl that is substituted with 0-2 R¹¹, wherein R¹¹ canbe C₁₋₃ alkyl, cyano, halo, C₁₋₄ alkoxy, or a 5-6 membered heterocyclylhaving 1 or 2 heteroatoms selected from nitrogen, oxygen or sulfur.Specific examples of R⁹ include F, Cl, or Br.

[0309] Yet another embodiment of the invention includes compounds ofFormula (XVII) having one or more of the following features:

[0310] (a) Z¹ is a carbon substituted with R⁷, Z² is a carbonsubstituted with R⁸, and R⁷ and R⁸ are taken together to form a fused,5-6 membered aromatic or nonaromatic ring having 0-2 ring heteroatomsselected from oxygen, nitrogen or sulfur;

[0311] (b) Z³ and Z⁵ are each CH;

[0312] (c) Z⁴ is a carbon substituted with R⁹;

[0313] (d) L₂ is a covalent bond;

[0314] (e) t is CH₂;

[0315] (f) s is CH₂; and

[0316] (g) R is hydrogen or C₁₋₈ alkyl that is substituted with 0-2 R¹¹.

[0317] In one aspect, the compound has all of the above features (a)-(g)and P¹, P², P³ and P⁴ are each independently selected from a substituted(e.g, CF) or unsubstituted (e.g., CH) carbon. In another aspect thecompound of Formula (XVII) has one or more of the features (a)-(g),wherein one or more of (h)-(k) are included:

[0318] (h) P¹, P², and P³ are each an unsubstituted carbon, and P⁴ is anunsubstituted carbon, or a carbon substituted with a halogen or alkoxy;

[0319] (i) R⁷ and R⁸ are taken together to form a substituted orunsubstituted benzo, furano, thieno, dioxolo ring.

[0320] (j) R⁹ is halo cyano or alkynyl; and

[0321] (k) R is hydrogen, or C₁₋₄ alkyl that is substituted with 0-2R¹¹, and R¹¹ is C₁₋₃ alkyl, cyano, halo, C₁₋₄ alkoxy, or a 5-6 memberedheterocyclyl having 1 or 2 heteroatoms selected from nitrogen, oxygen orsulfur. In still another aspect, the compound has all of features(a)-(k). In still a more specific aspect, P¹, P², and P³ are each anunsubstituted carbon and P⁴ is CH, CF, CCl, or CBr. In still anotheraspect, R⁷ and R⁸ are taken together to form a substituted orunsubstituted benzo, furano, thieno, dioxolo ring. Specific examples ofR⁹ include F, Cl, Br or cyano. In yet another aspect, R is C₁₋₄ alkylthat is substituted with 0-1 R¹¹ and R¹¹ is C₁₋₃ alkyl, cyano, halo, ora 5-6 membered heterocyclyl having 1 or 2 heteroatoms selected fromnitrogen, oxygen or sulfur.

[0322] In still a further embodiment, a compound of Formula (XVII) hasone or more of the following features:

[0323] (a) Z¹ is a carbon substituted with R⁷;

[0324] (b) Z², Z³ and Z⁵ are each CH;

[0325] (c) Z⁴ is a carbon substituted with R⁹;

[0326] (d) L is a covalent bond;

[0327] (e) t is CH₂or CHR³;

[0328] (f) s is CHR⁵, or CR⁵R⁶, and

[0329] (g) R is hydrogen or C₁₋₈ alkyl that is substituted with 0-2 R¹¹,wherein R³ and R⁵ are optionally taken together with their interveningatom or atoms to form a fused 3-7 membered aromatic or non-aromatic ringhaving 0-2 ring heteroatoms selected from oxygen, nitrogen, or sulfur orR and R⁵ are taken together with their intervening atoms to form a fusedpyrrolidino or piperidino ring.

[0330] In one aspect, the compound has all of the above features(a)-(g). In another aspect, the compound has one or more of the features(a)-(g) and one or more of features (h)-(k):

[0331] (h) P¹, P², and P³ are each an unsubstituted carbon, and P⁴ is anunsubstituted carbon, or a carbon substituted with a halogen or alkoxy;

[0332] (i) R⁷ is alkoxy;

[0333] (j) R⁹ is a halo, cyano or alkynyl; and

[0334] (k) s is CHR⁵. In certain aspects, R⁵ is taken together with R³to form a fused 5-6 membered non-aromatic ring. In other aspects, R⁵ istaken together with R with their intervening atoms to form a fusedpyrrolidino or piperidino ring. In a further aspect, the compound hasall of the features (h)-(k). In yet a more specific aspect, L is acovalent bond, P¹, P², and P³ are each CH, and P⁴ is an CH, CF, CCl, orCBr, R⁷ is alkoxy; t is CHR³; s is CHR⁵, wherein R⁵ is taken togetherwith R³ to form a fused 5-6 membered non-aromatic ring; Z¹ is a carbonsubstituted with R⁷; Z², Z³ and Z⁵ are each CH; Z⁴ is a carbonsubstituted with R⁹ and R⁹ is Br, Cl, F or cyano; and R is hydrogen orC₁₋₈ alkyl that is substituted with 0-2 R¹¹. In yet another morespecific aspect, L² is a covalent bond; P¹, P², and P³ are each CH, andP⁴ is an CH, CF, CCl, or CBr; R⁷ is alkoxy; s is CHR⁵, wherein R⁵ istaken together with R with their intervening atoms to form a fusedpyrrolidino or piperidino ring; t is CH₂; Z¹ is a carbon substitutedwith R⁷; Z², Z³ and Z⁵ are each CH; and Z⁴ is a carbon substituted withR⁹ and R⁹ is Br, Cl, F, or cyano.

[0335] Yet another embodiment of the invention includes compounds ofFormula (XVII) having one or more of the following features:

[0336] (a) Z¹ is a carbon substituted with R⁷, Z² is a carbonsubstituted with R⁸, and R⁷ and R⁸ are taken together to form a fused,5-6 membered aromatic or nonaromatic ring having 0-2 ring heteroatoms;

[0337] (b) Z³ and Z⁴ are each CH;

[0338] (c) Z⁵ is a carbon substituted with R⁹;

[0339] (d) L² is a covalent bond;

[0340] (e) t is CH₂ or CHR³;

[0341] (f) s is CUR⁵, or CR⁵R⁶, and

[0342] (g) R is hydrogen or C₁₋₈ alkyl that is substituted with 0-2 R¹¹.

[0343] In certain aspects, R³ and R⁵ can be taken together with theirintervening atom or atoms to form a fused 3-7 membered aromatic ornon-aromatic ring having 0-2 ring heteroatoms. Specific heteroatomsinclude oxygen, nitrogen, or sulfur. In other certain aspects, R and R⁵are taken together with their intervening atoms to form a fusedpyrrolidino or piperidino ring.

[0344] In one aspect the compound has all of the above features (a)-(g).In another aspect, the compound has one or more features (a)-(g), andP¹, P², and P³ are each an unsubstituted carbon, and P⁴ is anunsubstituted carbon, or a carbon substituted with a halogen or alkoxy.Examples of R⁹ include halo cyano or alkynyl. Specific R⁹ include Br,Cl, F or cyano. In one specific aspect, R⁷ and R⁸ are taken together toform a substituted or unsubstituted benzo, furano, thieno, dioxolo ring.In another specific aspect, s is CHR⁵, wherein R⁵ is taken together withR³ to form a fused 5-6 membered non-aromatic ring. In yet anotheraspect, s is CHR⁵, wherein R⁵ is taken together with R with theirintervening atoms to form a fused pyrrolidino or piperidino ring. In amore specific aspect, the compound has one or more features (a)-(g); P¹,P², and P³ are each an unsubstituted carbon, and P⁴ is an unsubstitutedcarbon, or a carbon substituted with a halogen or alkoxy; and one ormore of the following features (h)-(j):

[0345] (h) R⁷ and R⁸ are taken together to form a substituted orunsubstituted benzo, furano, thieno, dioxolo ring;

[0346] (i) R⁹ is halo cyano or alkynyl;

[0347] (j) s is CHR⁵, wherein R⁵ is taken together with R³ to form afused 5-6 membered non-aromatic ring or R⁵ is taken together with R withtheir intervening atoms to form a fused pyrrolidino or piperidino ring.In still another more aspect, the compound has all of the features of(a)-(j). In still a further aspect, the compound has all of the featuresof (a)-(j)wherein R⁵ is taken together with R³ to form a fused 5-6membered non-aromatic ring. In another another further specific aspect,the compound has all of the features of (a)-(j), wherein R⁵ is takentogether with R with their intervening atoms to form a fused pyrrolidinoor piperidino ring.

[0348] Another embodiment of the invention includes compounds of theFormula (XVII) having one or more of the following features:

[0349] (a) Z¹ is a carbon substituted with R⁷, Z² is a carbonsubstituted with R⁸, and R⁷ and R⁸ are taken together to form asubstituted or unsubstituted benzo, furano, thieno, dioxolo ring;

[0350] (b) Z³ and Z⁵ are each CH;

[0351] (c) Z⁴ is a carbon substituted with R⁹ and R⁹ is halo cyano oralkynyl;

[0352] (d) L² is a covalent bond;

[0353] (e) t is CH₂;

[0354] (f) s is CHR⁵;

[0355] (g) R and R⁵ are taken together with their intervening atoms toform a fused pyrrolidino or piperidino ring; and

[0356] (h) P¹, P², and P³ are each CH, and P⁴ is CH, CBr, CCl, CF, orC-alkoxy.

[0357] In one aspect, the compound has all of features (a)-(h).

[0358] Still a further embodiment of the invention includes compounds ofFormula (XVII) having one or more of the following features:

[0359] (a) Z¹ is a carbon substituted with R⁷, Z² is a carbonsubstituted with R⁸, and R⁷ and R⁸ are taken together to form asubstituted or unsubstituted benzo, furano, thieno, dioxolo ring;

[0360] (b) Z³ and Z⁴ are each CH;

[0361] (c) Z⁵ is a carbon substituted with R⁹ and R⁹ is halo cyano oralkynyl;

[0362] (d) L² is a covalent bond;

[0363] (e) t is CHR³;

[0364] (f) s is CHR⁵, wherein R³ and R⁵ are taken together with theirintervening atom or atoms to form a fused 3-7 membered non-aromatic ringhaving 0-2 ring heteroatoms selected from oxygen, nitrogen, or sulfur;

[0365] (g) R is hydrogen or C₁-₈ alkyl that is substituted with 0-2 R¹¹;and

[0366] (h) P¹, P², and P³ are each CH, and P⁴ is CH, CBr, CCl, CF, orC-alkoxy.

[0367] In one aspect, the invention includes compounds having all offeatures (a)-(h).

[0368] In a further embodiment, the MC4-R binding compounds of theinvention of formula VII do not include benzimadazole as the moiety offormula XIII, when P¹, P² P³, P⁴, Z¹, Z², Z⁴, Z³, and Z⁵ are each CH.Furthermore, in another further embodiment, the compounds of theinvention do not include compounds wherein the moiety of formula XIII istetrahydropyrimidine, when P¹, P², P³, P⁴, Z¹, Z², Z⁴, and Z⁵ are eachCH and Z³ is C—OEt or CH.

[0369] In another further embodiment, the MC4-R binding compounds of theinvention of formula VIII, do not include compounds wherein the moietyof formula XIII is benzoimidazolyl. In another further embodiment, theMC4-R binding compounds of the invention of formula VIII, do not includecompounds wherein P² is not Cl, if P¹, P³, or P⁴ are CH. In anotherfurther embodiment, the MC4-R binding compounds of the invention offormula VIII, do not include compounds wherein P¹, P²,P³, P⁴, Z¹, Z²,Z⁴, Z³, and Z⁵ are each CH, when the moiety of formula XIII istetrahydropyrimidine. In another further embodiment, the compounds offormula VIII of the invention do not include compounds wherein themoiety of formula is 4,5-dihydro-1H-imidazole, when P¹, P², P³, and P⁴are each CH, and wherein one or two of Z¹, Z², or Z³ is CCl, and theremaining Z groups are CH. In another further embodiments, the MC4-Rbinding compounds of formula VIII of the invention, do not includecompounds wherein the moiety of formula XIII is tetrahydropyrimidine,and when P¹, P², P³, and P⁴ are each CH, and Z² is CCl and the remainingZ groups are CH. In another further embodiments, the compounds offormula VIII of the invention, do not include compounds wherein when themoiety of formula XIII is tetrahydropyrimidine, and when P¹, P², P³, andP⁴ are each CH, and Z¹ and one of Z⁴ or Z⁵ are CCl and the remaining Zgroups are CH.

[0370] In another further embodiment, the MC4-R binding compounds of theinvention do not include compounds of formula XV, wherein the moiety offormula VIII is not benzoimidazole if P¹, P², P³, P⁴ are each CH, andwherein Z² is CMe and the remaining Z groups are CH.

[0371] In another further embodiment, the MC4-R binding compounds of theinvention do not include compounds of formula XVI, wherein the moiety offormula XVI, wherein L₂ is not NH (e.g., amino), if P¹, P², P³, P⁴, Z¹,Z², Z⁴, Z³, and Z⁵ are each CH. In another embodiment, the MC4-R bindingcompounds of formula XVI of the invention do not include compoundswherein P groups are substituted to form a naphthyl ring.

[0372] In another embodiment, the invention features a method fortreating an MC4-R associated state in a mammal by administering aneffective amount of a MC4-R binding compound to a mammal. Compounds offormula (X) are also included in the invention. In this embodiment, thecompound is of the formula (X):

[0373] wherein

[0374] Ar and Ar′ are aromatic groups;

[0375] R¹¹ is selected independently for each position capable ofsubstitution from the group hydrogen, cyano, nitro, alkoxy, halogen,alkyl, amino, or aryloxy.

[0376] R¹² is selected for each position capable of substitution fromthe group consisting of hydrogen, halogen, alkoxy, acetylenic, nitro,aryl, alkyl, alkenyl, alkynyl, cyano, acyl, or carbonyl;

[0377] R¹³ is hydrogen, alkenyl, alkynyl, aralkyl, nitro, cyano, alkyl(e.g., C₁-C₁₀ alkyl, e.g., methyl, ethyl, etc.) acyl, carbonyl, orSO₂CH₃, and may optionally be linked to an R¹⁶ or an R^(16′) group;

[0378] R¹⁶ and R^(16′) are each independently selected for each positioncapable of substitution from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, aryl, heterocyclic, carbonyl, or acyl, and mayoptionally be connected through an alkyl chain to R¹³ or another R¹⁶ orR^(16′) group, to form a fused or spiro ring system;

[0379] X is NR¹⁷, S, O or a covalent bond;

[0380] R¹⁷ is hydrogen, alkyl, alkenyl, alkynyl, acyl, heterocyclic, orcarbonyl;

[0381] R¹⁴ and R¹⁵ are each independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, heteroaromatic, halogen, nitro,cyano, amino, or aryl, for each occurrence;

[0382] w is 0, 1, 2, 3, or 4;

[0383] e is 0, 1, 2, or 3;

[0384] f is 0, 1, 2, or 3, and pharmaceutically acceptable saltsthereof.

[0385] Examples of Ar groups include:

[0386] wherein R¹⁸ is acyl, alkyl or hydrogen.

[0387] In a further embodiment, Ar is,

[0388] R¹¹ is selected independently for each aromatic position capableof substitution. Exemplary R¹¹ groups include, but are not limited to,hydrogen, halogen (e.g., fluorine, chlorine, or bromine), alkyl, amino,and benzyloxy.

[0389] Examples of Ar′ groups include:

[0390] wherein R¹⁹ is hydrogen, alkyl, acyl, aryl, alkenyl, or alkynyl.

[0391] In a further embodiment, each R¹² group is selected independentlyfrom the group consisting of hydrogen, alkoxy, halogen (e.g., fluorine,bromine, chlorine, or iodine), and cyano. Examples of alkoxy groupsinclude C₁-C₁₀ alkoxy, such as, methoxy, ethoxy, n-propoxy, i-propoxy,and cyclopentoxy.

[0392] Examples of X include covalent bond, S, O and NR⁷. Examples ofR¹⁷ include hydrogen, alkyl (e.g., C₁-C₁₀ alkyl, e.g., methyl), or acyl.

[0393] Examples of R¹⁶ and R^(16′) include alkyl and hydrogen. Each R¹⁶and R^(16′) group is selected independently for each occurrence. In afurther embodiment, at least one of R¹⁶ or R^(16′) are at least oncehydrogen. In another embodiment, at least one of R¹⁶ or R^(16′) are atleast once C₁-C₁₀ alkyl, e.g., methyl or ethyl.

[0394] In yet another further embodiment, R¹⁴ and R¹⁵ are eachindependently hydrogen, alkyl (e.g., C₁-C₁₀, e.g., methyl) or phenyl foreach occurrence.

[0395] In yet another further embodiment, R¹³ is hydrogen, acyl, alkyl(e.g., C₁-C₁₀ alkyl, e.g., methyl, ethyl, etc.) acyl, carboxy, orSO₂CH₃. Examples of acyl group include, but are not limited to,optionally substituted C₁-C₁₀alkyl acyl (e.g., i-propylcarbonyl andbenzylcarbonyl).

[0396] In yet another further embodiment, w is 2 or 3. In yet anotherfurther embodiment, e is 0 or 1. In yet another further embodiment, f is0 or 1.

[0397] In another embodiment, the invention features a method fortreating an MC4-R associated state in a mammal by administering aneffective amount of a MC4-R binding compound to a mammal. In thisembodiment, the compound is of the formula (XI):

[0398] wherein

[0399] Ar and Ar′ are aromatic groups, as described above;

[0400] R¹¹ is selected independently for each position capable ofsubstitution from the group hydrogen, halogen, alkyl, amino, cyano, oraryloxy.

[0401] R¹² is selected for each position capable of substitution fromthe group consisting of hydrogen, halogen, alkoxy, acetylenic, nitro,aryl, alkyl, alkenyl, alkynyl, cyano, acyl, or carbonyl;

[0402] X is NR¹⁷, S, O or a covalent bond;

[0403] R¹⁷ is hydrogen, alkyl, acyl, heterocyclic, or carbonyl;

[0404] R¹⁴ and R¹⁵ are each independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, or aryl, for each occurrence;

[0405] R²⁰ and R²¹ are each independently selected from the groupconsisting of substituted or unsubstituted alkyl, alkenyl, alkynyl,aryl, hydrogen, or carbonyl, and may optionally be linked to form aheterocycle (e.g., morphonlinyl, piperazinyl, piperidinyl, etc.);

[0406] v is 0, 1, 2, 3, 4, 5, or 6;

[0407] e is 0, 1, 2, or 3;

[0408] f is 0, 1, 2, or 3, and pharmaceutically acceptable saltsthereof.

[0409] Examples of Ar, Ar′, R¹¹, R¹², R¹⁴, R¹⁵ and X moieties includethose described for formula (X).

[0410] Other examples of MC4-R binding compounds include compounds ofthe formula (XVIII):

[0411] wherein

[0412] Ar and Ar′ are aromatic groups;

[0413] R¹¹ is selected independently for each position capable ofsubstitution from the group hydrogen, cyano, alkoxy, nitro, halogen,alkyl, amino, or aryloxy;

[0414] R¹² is selected for each position capable of substitution fromthe group consisting of hydrogen, halogen, alkoxy, acetylenic, nitro,aryl, alkyl, alkenyl, alkynyl, cyano, acyl, or carbonyl;

[0415] R¹³ is hydrogen, alkenyl, alkynyl, aralkyl, nitro, cyano, alkyl,acyl, carbonyl, or SO₂CH₃, and may optionally be linked to an R¹⁶ or anR^(16′) group;

[0416] R¹⁶ and R^(16′) are each independently selected for each positioncapable of substitution from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, hydroxyl, cyano, aryl, heterocyclic, carbonyl, oracyl, and may optionally be connected through an alkyl chain to R¹³ oranother R¹⁶ or R^(16′) group, to form a fused or spiro ring system;

[0417] X is NR¹⁷, S, O or a covalent bond;

[0418] R¹⁷ is hydrogen, alkyl, or carbonyl;

[0419] R¹⁴ and R¹⁵ are each independently hydrogen, halogen, or alky;

[0420] w is 1, 2, 3, or 4;

[0421] e is 0 or 1;

[0422] f is 0 or 1, wherein both e and f are not both 0 if X is acovalent bond, and pharmaceutically acceptable salts thereof.

[0423] Examples of Ar, Ar′, R¹¹, R¹², R¹⁴, R¹⁵, R¹⁶ and R^(16′) and Xmoieties include those described for formula (X).

[0424] The invention also pertains to the following compounds:

[0425] The invention also pertains to methods of using these compoundsin methods for treating MC4-R associated states in a mammal byadministering an effective amount of the compound to a mammal, such thatthe MC4-R associated state is treated, as well as pharmaceuticalcompositions comprising these compounds.

[0426] Other examples of MC4-R binding compounds include compounds ofthe formulae:

[0427] and pharmaceutically acceptable salts thereof.

[0428] Still further examples of MC4-R binding compounds includecompounds of the formulae:

[0429] and pharmaceutically acceptable salts thereof.

[0430] The invention also includes MC4-R binding compounds such as:

[0431]2-[2-(4-benzyloxy-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0432]2-[2-(2-iodo-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0433]2-[2-(2-methoxy-5-nitro-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0434]2-[2-(naphthalen-1-ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0435]2-[2-(3-chloro-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0436]2-[2-(2,5-dimethoxy-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0437]2-[2-(3-bromo-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0438] 2-[2-(2-iodo-benzylsulfanyl)-phenyl]-4,5-dihydro-1H-imidazole;

[0439]2-[2-(2-methoxy-5-nitro-benzylsulfanyl)-phenyl]-4,5-dihydro-1H-imidazole;

[0440]2-[2-(2-methoxy-5-nitro-benzyloxy)-phenyl]-1,4,5,6-tetrahydropyrimidine;

[0441]2-[2-(2-bromo-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0442]2-[2-(3-iodo-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0443]2-[2-(2-methoxy-5-nitro-benzylsulfanyl)-phenyl]-3a,4,5,6,7,7a-hexahydro-1H-benzoimidazole;

[0444]2-{2-[2-(2-methoxy-naphthalen-1-yl)-ethyl]-phenyl}-1,4,5,6-tetrahydropyrimidine;

[0445]2-[2-(5-bromo-2-methoxy-benzylsulfanyl)-phenyl]-1,4,5,6,-tetrahydropyrimidine;

[0446]2-{2-[2-(2-methyl-naphthalen-1-yl)-ethyl]-phenyl}-1,4,5,6-tetrahydropyrimidine;

[0447]2-{2-[2-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-ethyl]-phenyl}-1,4,5,6-tetrahydropyrimidine;

[0448]2-[2-(2-methoxy-napthalen-1-ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydropyrimidine;

[0449] 2-(2-Benzylsulfanyl-phenyl)-1,4,5,6-tetrahydro-pyrimidine;

[0450] 2-(2-Pentadecylsulfanyl-phenyl)-1,4,5,6-tetrahydro-pyrimidine;

[0451]2-(2-Cyclohexylmethylsulfanyl-phenyl)-1,4,5,6-tetrahydro-pyrimidine;

[0452]2-[2-(2-Methyl-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0453]2-[2-(3-Nitro-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0454]2-[2-(3,5-Dimethoxy-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0455]2-[2-(4-Fluoro-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0456]2-[2-(2-Chloro-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0457]2-[2-(2-Fluoro-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0458]2-[2-(2,4-Bis-trifluoromethyl-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0459]2-[2-(3-Methoxy-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0460]2-[2-(3,5-Bis-trifluoromethyl-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0461]2-[2-(2-Methoxy-5-nitro-benzyloxy)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0462]2-[2-(2-Chloro-6-fluoro-benzylsulfanyl)-phenyl]-4,5-dihydro-1H-imidazole;

[0463] 2-(2-Benzylsulfanyl-phenyl)-4,5-dihydro-1H-imidazole;

[0464]2-[2-(2,6-Difluoro-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0465]2-[2-(Naphthalen-1-ylmethoxy)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0466]2-[2-(2-Methyl-naphthalen-1-ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0467]1-{2-[2-(2-Chloro-6-fluoro-benzylsulfanyl)-phenyl]-5,6-dihydro-4H-pyrmidin-1-yl}-ethanone;

[0468]2-[2-(2-Chloro-6-fluoro-benzylsulfanyl)-phenyl]-3a,4,5,6,7,7a-hexahydro-1H-benzoimidazole;

[0469]2-[2-(2-Iodo-benzylsulfanyl)-phenyl]-3a,4,5,6,7,7a-hexahydro-1H-benzoimidazole;

[0470]2-[2-(2,5-Dimethyl-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0471]4-[2-(1,4,5,6-Tetrahydro-pyrimidin-2-yl)-phenylsulfanylmethyl]-quinoline;

[0472]2-[2-(2-Methoxy-5-nitro-benzylsulfanyl)-pyridin-3-yl]-1,4,5,6-tetrahydro-pyrimidine;

[0473]2-[2-(2-Methoxy-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0474]2-[2-(2-Cyclopentyloxy-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0475]2-[2-(2,3-Dihydro-benzo[1,4]dioxin-5-ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0476]2-[2-(6-Methoxy-2,3-dihydro-benzo[1,4]dioxin-5-ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0477]2-[2-(5-fluoro-2-methoxy-benzylsulfanyl)-phenyl]-4,5-dihydro-1H-imidazole;

[0478]1-Methyl-2-[2-(naphthalen-1-ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0479]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-phenyl]-4,5-dihydro-1H-imidazole;

[0480]2-[2-(5-Bromo-2-methoxy-benzyloxy)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0481]2-[2-(Naphthalen-1-yloxymethyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0482]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-phenyl]-5,5-dimethyl-1,4,5,6-tetrahydro-pyrimidine;

[0483]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-phenyl]-5,5-dimethyl-4,5-dihydro-1H-imidazole;

[0484]2-[2-(2,6-Dimethoxy-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0485]2-[2-(2-Bromo-6-methoxy-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0486]2-[5-Bromo-2-(5-bromo-2-methoxy-benzylsulfanyl)-phenyl]-4,5-dihydro-1H-imidazole;

[0487]2-[5-Bromo-2-(5-bromo-2-methoxy-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0488]2-[4-Bromo-2-(5-bromo-2-methoxy-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0489]2-[2-(2-Bromo-5-methoxy-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0490]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-5-methyl-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0491]2-[2-(Biphenyl-3-ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0492]2-[2-(5-Chloro-2-methoxy-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0493]2-[2-(2-Methoxy-5-thiophen-3-yl-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0494]2-[2-(Biphenyl-2-ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0495]2-[2-(5-Iodo-2-methoxy-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0496]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-5-fluoro-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0497]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0498]2-[2-(4,4′-Dimethoxy-biphenyl-3-ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0499]2-[2-(9H-Fluoren-9-ylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0500]2-[2-(3′-Chloro-4′-fluoro-4-methoxy-biphenyl-3-ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0501]2-[2-(1-Naphthalen-1-yl-ethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0502]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-5-fluoro-phenyl]-4,5-dihydro-1H-imidazole;

[0503] 2-(2-Benzhydrylsulfanyl-phenyl)-1,4,5,6-tetrahydro-pyrimidine;

[0504]2-[2-(2′-Fluoro-4″-methoxy-[1,1′;4′,1″]terphenyl-3″-ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0505] 2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzamidine;

[0506]2-[4-(Naphthalen-1-ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0507]2-[2-(5-Ethynyl-2-methoxy-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0508]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-1,4,5,6-tetrahydro-pyrimidine;

[0509]2-[2-(5-Bromo-2-cyclopentyloxy-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0510]2-[2-(5-Bromo-2-ethoxy-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0511]2-[2-(5-Bromo-2-propoxy-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0512] [2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-diethyl-amine;

[0513] 1-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-piperazine;

[0514]C-{4-[3-(5-Bromo-2-methoxy-benzylsulfanyl)-quinoxalin-2-yl]-morpholin-2-yl}-methylamine;

[0515]2-[2-(2-Methoxy-5-methyl-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0516]2-[2-(5-Bromo-2-methoxy-benzyloxymethyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0517] [2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-dimethyl-amine;

[0518]2-[2-(5-Bromo-2-isopropoxy-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0519]2-[2-(2-Ethoxy-naphthalen-1-ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0520]2-[2-(2-Propoxy-naphthalen-1-ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0521]4-Methoxy-3-[2-(1,4,5,6-tetrahydro-pyrimidin-2-yl)-phenylsulfanylmethyl]-benzonitrile;

[0522]1-{4-Methoxy-3-[2-(1,4,5,6-tetrahydro-pyrimidin-2-yl)-phenylsulfanylmethyl]-phenyl}-ethanone;

[0523]2-[2-(Naphthalen-1-ylsulfanylmethyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0524] 1-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-piperidine;

[0525]C-{4-[2-(2-Methoxy-naphthalen-1-ylmethylsulfanyl)-benzyl]-morpholin-2-yl}-methylamine;

[0526]1-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-pyrrolidin-3-ylamine;

[0527]1-[2-(2-Methoxy-naphthalen-1-ylmethylsulfanyl)-benzyl]-pyrrolidin-3-ylamine;

[0528]3-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-1,5,6,7,8,8a-hexahydro-imidazo[1,5-a]pyridine;

[0529]3-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-5,6,7,7a-tetrahydro-1H-pyrrolo[1,2-c]imidazole;

[0530]2-[2-(Benzo[b]thiophen-3-ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0531]2-[3-Fluoro-2-(naphthalen-1-ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0532]2-(Naphthalen-1-ylmethylsulfanyl)-3-(1,4,5,6-tetrahydro-pyrimidin-2-yl)-phenylamine;

[0533]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0534]2-[2-(2-Methoxy-phenylsulfanylmethyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0535]1-{2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-phenyl]-5,6-dihydro-4H-pyrimidin-1-yl}-3-methyl-butan-1-one;

[0536]1-{2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-phenyl]-5,6-dihydro-4H-pyrimidin-1-yl}-2-phenyl-ethanone;

[0537]2-[3-(5-Bromo-2-methoxy-benzylsulfanyl)-pyridin-2-yl]-1,4,5,6-tetrahydro-pyrimidine;

[0538] N-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-phenyl]-guanidine;

[0539]2-[2-(2-Isopropoxy-naphthalen-1-ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0540]2-[2-(2-Cyclopentyloxy-naphthalen-1-ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0541](5-Bromo-2-methoxy-benzyl)-[2-(1,4,5,6-tetrahydro-pyrimidin-2-yl)-phenyl]-amine;

[0542]2-[2-(5-Bromo-2-methoxy-benzylsulfanylmethyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0543]2-[2-(2-Methoxy-naphthalen-1-ylsulfanylmethyl)-pheny]-1,4,5,6-tetrahydro-pyrimidine;

[0544]2-[3-(5-Bromo-2-methoxy-benzylsulfanyl)-pyrazin-2-yl]-1,4,5,6-tetrahydro-pyrimidine;

[0545]2-[3-Chloro-2-(naphthalen-1-ylsulfanylmethyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0546]2-[2-(6-Bromo-2-methoxy-naphthalen-1-ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0547]2-[3-Chloro-2-(2-methoxy-naphthalen-1-ylsulfanylmethyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0548]2-[2-(5-Bromo-2-methoxy-phenylsulfanylmethyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0549]2-[2-(5-Bromo-2-methoxy-phenylsulfanylmethyl)-3-chloro-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0550]2-[1-(2-Naphthalen-1-yl-ethyl)-1H-pyrrol-2-yl]-1,4,5,6-tetrahydro-pyrimidine;

[0551](5-Bromo-2-methoxy-benzyl)-methyl-[2-(1,4,5,6-tetrahydro-pyrimidin-2-yl)-phenyl]-amine;

[0552] 2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzylamine;

[0553]2-[2-(2-Chloro-phenylsulfanylmethyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0554]2-[2-(2-Bromo-phenylsulfanylmethyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0555] 2-(2-o-Tolylsulfanylmethyl-phenyl)-1,4,5,6-tetrahydro-pyrimidine;

[0556]2-[2-(2,5-Dichloro-phenylsulfanylmethyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0557]2-(3-Amino-propylamino)-6-(5-bromo-2-methoxy-benzylsulfanyl)-benzonitrile;

[0558]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-1,4,5,6-tetrahydro-pyrimidine;

[0559] [2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-diethyl-amine;

[0560] 4-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-morpholine;

[0561]3′-(5-Bromo-2-methoxy-benzylsulfanyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl;

[0562]2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-piperazin-1-yl-6,7-dihydro-quinoxaline;

[0563] 1-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-piperidine;

[0564] C-{4-[2-(2-Methoxy-naphthalen-1-ylmethylsulfanyl)-benzyl]-morpholin-2-yl}-methylamine;

[0565]1-[3-(5-Bromo-2-methoxy-benzylsulfanyl)-pyrazin-2-yl]-pyrrolidin-3-ylamine;

[0566]1-[3-(5-Bromo-2-methoxy-benzylsulfanyl)-quinoxalin-2-yl]-pyrrolidin-3-ylamine;

[0567]1-[2-(2-Methoxy-naphthalen-1-ylmethylsulfanyl)-benzyl]-pyrrolidin-3-ylamine;

[0568]C-{4-[3-(5-Bromo-2-methoxy-benzylsulfanyl)-pyrazin-2-yl]-morpholin-3-yl}-methylamine;

[0569] 1-[3-Fluoro-2-(2-naphthalen-1-yl-ethyl)-benzyl]-piperazine;

[0570]1-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzyl]-azetidine;

[0571]1-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzyl]-pyrrolidin-3-ol;

[0572] [2-(Naphthalen-1-ylmethylsulfanyl)-phenyl]-carbamic acid1-aza-bicyclo[2.2.2]oct-3-yl ester;

[0573] [2-(2-Methyl-naphthalen-1-ylmethylsulfanyl)-phenyl]-carbamic acid1-aza-bicyclo[2.2.2]oct-3-yl ester;

[0574] [2-(2-Methyl-naphthalen-1-ylmethylsulfanyl)-phenyl]-carbamic acid2-piperidin-1-yl-ethyl ester;

[0575]{1-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzyl]-pyrrolidin-2-yl}-methanol;

[0576]4-tert-Butyl-N-naphthalen-1-ylmethyl-N-(2-piperidin-1-yl-ethyl)-benzamide;

[0577]N,N-Dimethyl-N′-naphthalen-2-ylmethyl-N′-naphthalen-1-ylmethyl-propane-1,3-diamine;

[0578]N-(5-Bromo-2-methoxy-benzyl)-N′,N′-dimethyl-N-naphthalen-1-ylmethyl-propane-1,3-diamine;

[0579] 1-Naphthalen-1-ylmethyl-3-phenethyl-l-(2-piperidin-1-yl-ethyl)-thiourea;

[0580]3-(4-Dimethylamino-phenyl)-1-(3-dimethylamino-propyl)-1-naphthalen-1-ylmethyl-thiourea;

[0581]4-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzylamino]-piperidine-1-carboxylicacid ethyl ester;

[0582] 2-[2-(2-Naphthalen-1-yl-ethyl)-phenyl]-ethylamine;

[0583] Naphthalene-2-sulfonic acid(2-dimethylamino-ethyl)-naphthalen-1-ylmethyl-amide;

[0584]1-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzyl]-2-methoxymethyl-pyrrolidine;

[0585] (2-Hexyloxy-phenyl)-carbamic acid2-piperidin-1-yl-1-piperidin-1-ylmethyl-ethyl ester;

[0586] 3-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyloxy]-pyrrolidine;

[0587]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyloxymethyl]-pyrrolidine;

[0588] 2-[2-(Naphthalen-1-ylsulfanylmethyl)-phenyl]-piperidine;

[0589] 3-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzylamino]-propan-1-ol;

[0590]3-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzylamino]-3-methyl-butan-1-ol;

[0591] 1-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-pyrrolidin-3-ol;

[0592]{1-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-pyrrolidin-2-yl}-methanol;

[0593]{1-[2-(Naphthalen-1-ylsulfanylmethyl)-benzyl]-piperidin-2-yl}-methanol;

[0594]2-[2-(Naphthalen-1-ylsulfanylmethyl)-pyrrolidin-1-yl]-ethyl-N-pyrrolidine;

[0595]N-pyrrolyl-[1-(2-naphthalen-1-yl-ethyl)-pyrrolidin-2-ylmethyl]-amine;

[0596] 1-(2-Naphthalen-1-yl-ethyl)-piperidine-2-carboxylic acid methylester;

[0597](3-Bromo-benzyl)-(1-ethyl-pyrrolidin-2-ylmethyl)-naphthalen-1-ylmethyl-amine;

[0598] 3-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyloxy]-piperidine;

[0599](5-Bromo-2-methoxy-benzyl)-(1-ethyl-pyrrolidin-2-ylmethyl)-naphthalen-1-ylmethyl-amine;

[0600](1-Ethyl-pyrrolidin-2-ylmethyl)-naphthalen-2-ylmethyl-naphthalen-1-ylmethyl-amine;

[0601]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyloxymethyl]-pyrrolidine;

[0602](3-Bromo-benzyl)-(3-imidazol-1-yl-propyl)-naphthalen-1-ylmethyl-amine;

[0603](3-Imidazol-1-yl-propyl)-naphthalen-2-ylmethyl-naphthalen-1-ylmethyl-amine;

[0604] [2-(Naphthalen 1-ylmethylsulfanyl)-phenyl]-carbamic acid2-pipenidin-1-yl-1-piperidin-1-ylmethyl-ethyl ester;

[0605] [2-(Naphthalen-1-ylmethylsulfanyl)-phenyl]-carbamic acid2-dimethylamino-ethyl ester;

[0606] 1-[2-(Naphthalen-1-ylsulfanylmethyl)-benzyl]-piperazine;

[0607][3-(2-Methyl-piperidin-1-yl)-propyl]-[2-(naphthalen-1-ylsulfanylmethyl)-benzyl]-amine;

[0608] 1-[3-Chloro-2-(naphthalen-1-ylsulfanylmethyl)-benzyl]-piperazine;

[0609]N,N-Dimethyl-N′-(2-naphthalen-1-yl-ethyl)-N′-naphthalen-1-ylmethyl-ethane-1,2-diamine;

[0610]{1-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzyl]-piperidin-2-yl}-methanol;

[0611] 1-[2-(2-Naphthalen-1-yl-ethyl)-benzyl]-piperazine;

[0612][3-(2-Methyl-piperidin-1-yl)-propyl]-[2-(2-naphthalen-1-yl-ethyl)-benzyl]-amine;

[0613] 1-[3-Fluoro-2-(2-naphthalen-1-yl-ethyl)-benzyl]-piperazine;

[0614]{1-[3-Chloro-2-(naphthalen-1-ylsulfanylmethyl)-benzyl]-piperidin-2-yl}-methanol;

[0615]{1-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzyl]-piperidin-2-yl}-methanol;

[0616] {1-[2-(2-Naphthalen-1-yl-ethyl)-benzyl]-piperidin-2-yl}-methanol;

[0617][3-(2-Methyl-piperidin-1-yl)-propyl]-[2-(2-naphthalen-1-yl-ethyl)-benzyl]-amine;

[0618] 1-[2-(2-Naphthalen-1-yl-ethyl)-benzyl]-pyrrolidin-3-ylamine;

[0619]1-Phenyl-3-piperazin-1-yl-5,6,7,8-tetrahydro-isoquinoline-4-carbonitrile;

[0620] 2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-phenyl]-6-ethyl-1,4,5,6-tetrahydro-pyrimidine;

[0621]2-[2-(4-Methoxy-biphenyl-3-ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0622]2-[2-(2-Methoxy-5-phenylethynyl-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0623]2-[2-(2-Naphthalen-1-yl-ethyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0624]2-[3-(2-Methoxy-naphthalen-1-ylsulfanylmethyl)-thiophen-2-yl]-1,4,5,6-tetrahydro-pyrimidine;

[0625]2-[2-(2,5-Dimethoxy-phenylsulfanylmethyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0626]2-[2-(4-Methyl-naphthalen-1-ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0627]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-4,4-dimethyl-4,5-dihydro-1H-imidazole;

[0628]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-5,5-dimethyl-1,4,5,6-tetrahydro-pyrimidine;

[0629]2-[3-(Naphthalen-1-ylsulfanylmethyl)-thiophen-2-yl]-1,4,5,6-tetrahydro-pyrimidine;

[0630]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-phenyl}-1,4,5,6-tetrahydro-pyrimidine;

[0631]2-[3-Chloro-2-(2-naphthalen-1-yl-ethyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0632]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-phenyl}-1,4,5,6-tetrahydro-pyrimidine;

[0633]2-[2-(5-Bromo-2-methoxy-phenylsulfanylmethyl)-3-fluoro-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0634]2-[2-(Naphthalen-1-ylsulfanylmethyl)-phenyl]-4,5-dihydro-1H-imidazole;

[0635]2-[3-Fluoro-2-(naphthalen-1-ylsulfanylmethyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0636]2-[3-Bromo-2-(naphthalen-1-ylsulfanylmethyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0637]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-1,4,5,6-tetrahydro-pyrimidine;

[0638]2-[2-(2-Methoxy-5-trifluoromethyl-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0639]2-[4-(Naphthalen-1-ylsulfanylmethyl)-thiophen-3-yl]-1,4,5,6-tetrahydro-pyrimidine;

[0640]2-[2-(Naphthalen-1-ylsulfanylmethyl)-thiophen-3-yl]-1,4,5,6-tetrahydro-pyrimidine;

[0641]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-trifluoromethyl-phenyl}-1,4,5,6-tetrahydro-pyrimidine;

[0642]2-[2-(2-Naphthalen-1-yl-ethyl)-3-trifluoromethyl-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0643]2-[2-(6-Fluoro-naphthalen-1-ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0644]{1-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-piperidin-2-yl}-methanol;

[0645]2-[3-Fluoro-2-(2-naphthalen-1-yl-ethyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0646][2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzyl]-[3-(2-methyl-piperidin-1-yl)-propyl]-amine;

[0647]1-[2-(-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzyl]-pyrrolidin-3-ylamine;

[0648]1-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzyl]-piperazine;

[0649]5,5-Dimethyl-2-[2-(2-naphthalen-1-yl-ethyl)-phenyl]-4,5-dihydro-1H-imidazole;

[0650]2-[3-Fluoro-2-(2-naphthalen-1-yl-ethyl)-phenyl]-5,5-dimethyl-4,5-dihydro-1H-imidazole;

[0651]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3,5-difluoro-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0652]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3,5-difluoro-phenyl]-5,5-dimethyl-4,5-dihydro-1H-imidazole;

[0653]3-(2-Naphthalen-1-yl-ethyl)-2-(1,4,5,6-tetrahydro-pyrimidin-2-yl)-phenylamine;

[0654] Amino-[2-(2-naphthalen-1-yl-ethyl)-phenyl]-acetonitrile;

[0655] 1-[2-(2-Naphthalen-1-yl-ethyl)-phenyl]-ethane-1,2-diamine;

[0656]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-phenyl]-4-methyl-4,5-dihydro-1H-imidazole;

[0657]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-4-methyl-4,5-dihydro-1H-imidazole;

[0658]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-phenyl]-4-methyl-4,5-dihydro-1H-imidazole;

[0659]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3,4-difluoro-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0660]2-[3-Fluoro-2-(naphthalen-1-ylsulfanylmethyl)-phenyl]-5,5-dimethyl-4,5-dihydro-1H-imidazole;

[0661]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-1-methyl-ethyl]-phenyl}-1,4,5,6-tetrahydro-pyrimidine;

[0662] 2-[2-(5-Bromo-2-methoxy benzylsulfanyl)-3-fluoro-4-trifluoromethyl-phenyl]-4,4-dimethyl-4,5-dihydro-1H-imidazole;

[0663] 2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-4-trifluoromethyl-phenyl]-5,5-dimethyl-1,4,5,6-tetrahydro-pyrimidine;

[0664]2-[3-Methoxy-2-(2-naphthalen-1-yl-ethyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0665]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-phenyl]-1,4,5,6-tetrahydro-pyrimidin-5-ol;

[0666]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-methoxy-phenyl}-1,4,5,6-tetrahydro-pyrimidine;

[0667]1-Amino-3-[2-(5-bromo-2-methoxy-phenyl)-7-chloro-benzo[b]thiophen-3-ylamino]-propan-2-ol;

[0668]2-[2-(1-Methyl-2-naphthalen-1-yl-ethyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0669]3-(5-Bromo-2-methoxy-benzylsulfanyl)-2-fluoro-4-(1,4,5,6-tetrahydro-pyrimidin-2-yl)-phenylamine;

[0670]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-methyl-phenyl}-1,4,5,6-tetrahydro-pyrimidine;

[0671]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-1,4,5,6-tetrahydro-pyrimidin-5-ol;

[0672]1-Amino-3-[2-(5-bromo-2-methoxy-phenyl)-7-fluoro-benzo[b]thiophen-3-ylamino]-propan-2-ol;

[0673] 2-[3-Methoxy-2-(naphthalen-1-ylsulfanylmethyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0674]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-1,4,5,6-tetrahydro-pyrimidin-5-ol;

[0675]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-5-methoxy-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0676]2-{2-[2-Chloro-6-(1,4,5,6-tetrahydro-pyrimidin-2-yl)-phenyl]-ethyl}-phenol;

[0677]2-[3-Methoxy-2-(naphthalen-1-ylsulfanylmethyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidin-5-ol;

[0678]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-methyl-phenyl}-5-methyl-4,5dihydro-1H-imidazole;

[0679]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-methyl-phenyl}-1,4,5,6-tetrahydro-pyrimidin-5-ol;

[0680]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3,4-difluoro-phenyl]-1,4,5,6-tetrahydro-pyrimidin-5-ol;

[0681]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,4-dimethyl-4,5-dihydro-1H-imidazole;

[0682]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-4-methyl-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0683]4,4-Dimethyl-2-[2-(naphthalen-1-ylmethylsulfanyl)-phenyl]-4,5-dihydro-oxazole;

[0684]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-4-methoxy-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0685]2-[5-(5-Bromo-2-methoxy-benzyl)-2-methyl-thiophen-3-yl]-1,4,5,6-tetrahydro-pyrmidine;

[0686]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-thiophen-3-yl}-1,4,5,6-tetrahydro-pyrimidine;

[0687]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-ethoxy-phenyl}-1,4,5,6-tetrahydro-pyrmidine;

[0688]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-isopropoxy-phenyl}-1,4,5,6-tetrahydro-pyrimidine;

[0689]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-4-methoxy-phenyl}-1,4,5,6-tetrahydro-pyrimidine;

[0690]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-isopropoxy-phenyl}-1,4,5,6-tetrahydro-pyrimidin-5-ol;

[0691]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-methoxy-phenyl}-1,4,5,6-tetrahydro-pyrimidin-5-ol;

[0692]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-4-methoxy-phenyl}-1,4,5,6-tetrahydro-pyrimidine;

[0693]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-ethoxy-phenyl}-1,4,5,6-tetrahydro-pyrimidin-5-ol;

[0694]2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-(1,4,5,6-tetrahydro-pyrimidin-2-yl)-benzonitrile;

[0695]2-{3-Benzyloxy-2-[2-(5-bromo-2-methoxy-phenyl)-ethyl]-phenyl}-1,4,5,6-tetrahydro-pyrimidine;

[0696]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-4-butyl-phenyl}-1,4,5,6-tetrahydro-pyrimidine;

[0697]2-{5-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-1,4,5,6-tetrahydro-pyrimidine;

[0698]2-{5-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-8-chloro-2,3-dihydro-benzo[1,4]dioxin-6-yl}-1,4,5,6-tetrahydro-pyrimidine;

[0699]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-ethyl-phenyl}-1,4,5,6-tetrahydro-pyrimidine;

[0700]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-propyl-phenyl}-1,4,5,6-tetrahydro-pyrimidine;

[0701]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-butoxy-phenyl}-1,4,5,6-tetrahydro-pyrimidine;

[0702]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-isobutoxy-phenyl}-1,4,5,6-tetrahydro-pyrimidine;

[0703]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-butoxy-phenyl}-1,4,5,6-tetrahydro-pyrimidin-5-ol;

[0704]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-5-methoxy-1,4,5,6-tetrahydro-pyrimidine;

[0705]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-1-methyl-1,4,5,6-tetrahydro-pyrimidine;

[0706]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-1-methyl-4,5-dihydro-1H-imidazole;

[0707][2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-1-methyl-4,5-dihydro-1H-imidazole;

[0708]2-{2-[3-(1,4,5,6-Tetrahydro-pyrimidin-2-yl)-biphenyl-2-yl]-ethyl}-phenol;

[0709]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-1-methyl-4,5-dihydro-1H-imidazole;

[0710]N-(3-Amino-propyl)-2-[2-(5-bromo-2-methoxy-phenyl)-ethyl]-6-methoxy-benzamide;

[0711]N-(3-Amino-propyl)-2-[2-(5-bromo-2-methoxy-phenyl)-ethyl]-6-methyl-benzamide;

[0712]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-5,6-dihydro-4H-pyrimidine-1-carboxylicacid 1-acetoxy-2-methyl-propyl ester;

[0713]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-5,6-dihydro-4H-pyrimidine-1-carboxylicacid 1-acetoxy-ethyl ester;

[0714]3-(5-Bromo-2-methoxy-phenyl)-5-chloro-3,4-dihydro-isoquinolin-1-ylamine;

[0715]2-[2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-(4-methoxy-benzyloxy)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[0716]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-5-methyl-1,4,5,6-tetrahydro-pyrimidin-5-ol;

[0717]2-[(5-Bromo-2-methoxy-phenyl)-(3-piperidin-1-yl-propylamino)-methyl]-3-chloro-6-methyl-phenol;

[0718]1-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-methyl-benzyl}-piperazine;

[0719]1-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-methyl-benzyl}-4-methyl-piperazine;

[0720]1-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-methyl-benzyl}-piperidine;

[0721]{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-methyl-benzyl}-diethyl-amine;

[0722] 3-(5-Bromo-2-methoxy-phenyl)-1,2,3,4-tetrahydro-isoquinoline;

[0723]1-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-benzyl}-piperazine;

[0724]1-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-benzyl}-4-methyl-piperazine;

[0725]1-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-benzyl}-piperidine;

[0726]{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-benzyl}-diethyl-amine;

[0727]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-1H-imidazole;

[0728](1-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-benzyl}-piperidin-2-yl)-methanol;

[0729]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-propoxy-phenyl}-1,4,5,6-tetrahydro-pyrimidine;

[0730]1-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-4-methyl-piperazine;

[0731]1-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-chloro-benzyl}-piperazine;

[0732]1-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-chloro-benzyl}-4-methyl-piperazine;

[0733]1-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-chloro-benzyl}-piperidine;

[0734]{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-chloro-benzyl}-diethyl-amine;

[0735]1-(5-Bromo-2-methoxy-benzyl)-2-(4-methoxy-benzyl)-2,3-dihydro-1H-isoindole;

[0736]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-5,6-dihydro-4H-pyrimidine-1-carboxylicacid 1-acetoxy-ethyl ester;

[0737]1-(2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}1-5,6-dihydro-4H-pyrimidin-1-yl)-ethanone;

[0738]1-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-benzyl}-4-methyl-piperazine;

[0739]{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-benzyl}-diethyl-amine;

[0740]1-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-benzyl}-piperidine;

[0741](1-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-benzyl}-piperidin-2-yl)-methanol;

[0742]4-Fluoro-N-{2-[4-(2-methoxy-phenyl)-piperazin-1-yl]-ethyl}-N-pyridin-2-yl-benzamide;

[0743]3-(5-Bromo-2-methoxy-phenyl)-2-methyl-1,2,3,4-tetrahydro-isoquinoline;

[0744]1-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-benzyl}-piperazine;

[0745]1-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-benzyl}-4-methyl-piperazine;

[0746]1-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-benzyl}-piperidine;

[0747]{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-benzyl}-diethyl-amine;

[0748]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-1H-imidazole;

[0749](1-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-benzyl}-piperidin-2-yl)-methanol;

[0750]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-propoxy-phenyl}-1,4,5,6-tetrahydro-pyrimidine;

[0751]1-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-4-methyl-piperazine;

[0752]1-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-chloro-benzyl}-piperazine;

[0753]1-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-chloro-benzyl}-4-methyl-piperazine;

[0754]1-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-chloro-benzyl}-piperidine;

[0755]{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-chloro-benzyl}-diethyl-amine;

[0756]1-(5-Bromo-2-methoxy-benzyl)-2-(4-methoxy-benzyl)-2,3-dihydro-1H-isoindole;

[0757]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-5,6-dihydro-4H-pyrimidine-1-carboxylicacid 1-acetoxy-ethyl ester;

[0758]1-(2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-5,6-dihydro-4H-pyrimidin-1-yl)-ethanone;

[0759]1-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-benzyl}-4-methyl-piperazine;

[0760]{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-benzyl}-diethyl-amine;

[0761]1-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-benzyl}-piperidine;

[0762]4-Fluoro-N-{2-[4-(2-methoxy-phenyl)-piperazin-1-yl]-ethyl}-N-pyridin-2-yl-benzamide;

[0763]3-(5-Bromo-2-methoxy-phenyl)-2-methyl-1,2,3,4-tetrahydro-isoquinoline;

[0764]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-1-ethyl-4,5-dihydro-1H-imidazole;

[0765]{2-[3-(5-Bromo-2-methoxy-phenyl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-diethyl-amine;

[0766]1-(2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-imidazol-1-yl)-ethanone;

[0767]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-imidazole-1-carboxylicacid ethyl ester;

[0768]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-imidazole-1-carboxylicacid isobutyl ester;

[0769]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-imidazole-1-carboxylicacid tert-butyl ester;

[0770]1-(2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-imidazol-1-yl)-2,2-dimethyl-propan-1-one;

[0771] 1-(5-Bromo-2-methoxy-benzyl)-2,3-dihydro-1H-isoindole;

[0772] 1-(2-Methoxy-benzyl)-2-methyl-2,3-dihydro-1H-isoindole;

[0773] 2-Methyl-1-naphthalen-1-ylmethyl-2,3-dihydro-1H-isoindole;

[0774]1-{2-[3-Chloro-2-(2-naphthalen-1-yl-ethyl)-phenyl]-4,5-dihydro-imidazol-1-yl}-2,2-dimethyl-propan-1-one;

[0775]{2-[1-(5-Bromo-2-methoxy-benzyl)-1,3-dihydro-isoindol-2-yl]-ethyl}-diethyl-amine;

[0776]2-[3-Chloro-2-(2-naphthalen-1-yl-ethyl)-phenyl]-1-methyl-1,4,5,6-tetrahydro-pyrimidine;

[0777]2-[3-Chloro-2-(2-naphthalen-1-yl-ethyl)-phenyl]-5,6-dihydro-4H-pyrimidine-1-carboxylicacid tert-butyl ester;

[0778]2-[3-Chloro-2-(2-naphthalen-1-yl-ethyl)-phenyl]-4,5-dihydro-1H-imidazole;

[0779]1-{2-[3-Chloro-2-(2-naphthalen-1-yl-ethyl)-phenyl]-4,5-dihydro-imidazol-1-yl}-ethanone;

[0780]2-[3-Chloro-2-(2-naphthalen-1-yl-ethyl)-phenyl]-4,5-dihydro-imidazole-1-carboxylicacid isobutyl ester;

[0781]2-[3-Chloro-2-(2-naphthalen-1-yl-ethyl)-phenyl]-4,5-dihydro-imidazole-1-carboxylicacid tert-butyl ester;

[0782]2-[3-Chloro-2-(2-naphthalen-1-yl-ethyl)-phenyl]-4,5-dihydro-imidazole-1-carboxylicacid ethyl ester;

[0783]2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-N-(3-formylamino-propyl)-6-methyl-benzamide;

[0784]2-[3-Chloro-2-(2-naphthalen-1-yl-ethyl)-phenyl]-1-ethyl-4,5-dihydro-1H-imidazole;

[0785]1-(2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-5,6-dihydro-4H-pyrimidin-1-yl)-2,2-dimethyl-propan-1-one;

[0786]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-thiophen-3-yl}-4,5-dihydro-1H-imidazole;

[0787]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-5,6-dihydro-4H-pyrimidine-1-carboxylicacid isobutyl ester;

[0788]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-1-isocyanomethyl-4,5-dihydro-1H-imidazole;

[0789]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-thiophen-3-yl}-1-methyl-4,5-dihydro-1H-imidazole;

[0790]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-thiophen-3-yl}-1-ethyl-4,5-dihydro-1H-imidazole;

[0791] 3-(5-Bromo-2-methoxy-benzyl)-2-methyl-2,3-dihydro-isoindol-1-one;

[0792]4-(2-Methoxy-benzyl)-2-(4-methoxy-benzyl)-1,2,3,4-tetrahydro-isoquinoline;

[0793]4-(5-Bromo-2-methoxy-benzyl)-2-(4-methoxy-benzyl)-1,2,3,4-tetrahydro-isoquinoline;

[0794]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-1-propyl-4,5-dihydro-1H-imidazole;

[0795]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-3a,4,5,6,7,7a-hexahydro-1H-benzoimidazole;

[0796]5,5-Dimethyl-2-[2-(naphthalen-1-ylsulfanylmethyl)-phenyl]-4,5-dihydro-1H-imidazole;

[0797]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-phenyl]-4,4-dimethyl-4,5-dihydro-1H-imidazole;

[0798]N-(5-Bromo-2-methoxy-benzyl)-N′-methyl-N-naphthalen-1-ylmethyl-ethane-1,2-diamine;

[0799]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-1-ethyl-1,4,5,6-tetrahydro-pyrimidine;

[0800]2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-N,N,N′-trimethyl-benzamidine;

[0801]2-[3-Chloro-2-(2-naphthalen-1-yl-ethyl)-phenyl]-1-methyl-4,5-dihydro-1H-imidazole;

[0802]1-Benzyl-2-{2-[2-(5-bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-1H-imidazole;

[0803]({2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-pyrrolidin-1-yl-methylene)-methyl-amine;

[0804]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-1-isopropyl-4,5-dihydro-1H-imidazole;

[0805]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-1-(2,2,2-trifluoro-ethyl)-4,5-dihydro-1H-imidazole;

[0806]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-phenyl]-6-ethyl-1,4,5,6-tetrahydro-pyrimidine;

[0807]2-(2-Benzylsulfanyl-phenyl)-3a,4,5,6,7,7a-hexahydro-1H-benzoimidazole;

[0808]2-[2-(2-Chloro-6-fluoro-benzylsulfanyl)-phenyl]-3a,4,5,6,7,7a-hexahydro-1H-benzoimidazole;

[0809]2-[2-(2-Iodo-benzylsulfanyl)-phenyl]-3a,4,5,6,7,7a-hexahydro-1H-benzoimidazole;

[0810] 2-[2-(2-Methoxy-5-nitro-benzyl sulfanyl)-phenyl]-3a,4,5,6,7,7a-hexahydro-1H-benzoimidazole;

[0811]3-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-1,5,6,7,8,8a-hexahydro-imidazo[1,5-a]pyridine;

[0812]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-phenyl}-4,5-dihydro-1H-imidazole;

[0813]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-ethoxy-phenyl}-1-ethyl-4,5-dihydro-1H-imidazole;

[0814]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-ethoxy-phenyl}-4,5-dihydro-1H-imidazole;

[0815]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-ethoxy-phenyl}-1-methyl-4,5-dihydro-1H-imidazole;

[0816]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-methoxy-phenyl}-1-methyl-4,5-dihydro-1H-imidazole;

[0817]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-phenyl}-1-ethyl-4,5-dihydro-1H-imidazole;

[0818] 2-[2-(2-Naphthalen-1-yl-ethyl)-phenyl]-4,5-dihydro-1H-imidazole;

[0819]1-Ethyl-2-[2-(2-naphthalen-1-yl-ethyl)-phenyl]-4,5-dihydro-1H-imidazole;

[0820]1-Methyl-2-[2-(2-naphthalen-1-yl-ethyl)-phenyl]-4,5-dihydro-1H-imidazole;

[0821]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-phenyl}-1-ethyl-4,5-dihydro-1H-imidazole;

[0822]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[0823]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-methyl-phenyl}-4,5-dihydro-1H-imidazole;

[0824]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-phenyl}-1-methyl-4,5-dihydro-1H-imidazole;

[0825]3-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-5,6-dihydro-imidazo[2,1-b]thiazole;

[0826]1-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-2-(4,4-dimethyl-4,5-dihydro-1H-imidazol-2-ylsulfanyl)-ethanone;

[0827]3-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-6,6-dimethyl-5,6-dihydro-imnidazo[2,1-b]thiazole;

[0828]{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-benzyl}-(4,5-dihydro-1H-imidazol-2-yl)-amine;

[0829]{3-Chloro-2-[2-(2-methoxy-phenyl)-ethyl]-benzyl}-(4,5-dihydro-1H-imidazol-2-yl)-amine;

[0830](2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-imidazol-1-yl)-aceticacid;

[0831](2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-3a,4,5,6,7,7a-hexahydro-benzoimidazol-1-yl)-acetonitrile;

[0832]3-(2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-imidazol-1-yl)-propionitrile;

[0833] 2-(3-Fluoro-2-phenethyl-phenyl)-4,5-dihydro-1H-imidazole;

[0834]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-1-propyl-3a,4,5,6,7,7a-hexahydro-1H-benzoimidazole;

[0835]3-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-1,5,6,7,8,8a-hexahydro-imidazo[1,5-a]pyridine;

[0836]3-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-5,6,7,7a-tetrahydro-1H-pyrrolo[1,2-c]imidazole;

[0837]3-(2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-imidazol-1-yl)-2-methyl-propionitrile;

[0838]2-{2-[2-(2-Methyl-naphthalen-1-yl)-ethyl]-phenyl}-3a,4,5,6,7,7a-hexahydro-1H-benzoimidazole;

[0839]2-{2-[2-(2-Methyl-naphthalen-1-yl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[0840]2-[2-(2-Naphthalen-1-yl-ethyl)-phenyl]-3a,4,5,6,7,7a-hexahydro-1H-benzoimidazole;

[0841]2-{2-[2-(2-Methoxy-naphthalen-1-yl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[0842]2-(1-Isopropyl-4,5-dihydro-1H-imidazol-2-yl)-3-(2-naphthalen-1-yl-ethyl)-pyridine;

[0843]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-thiophen-3-yl}-1-propyl-4,5-dihydro-1H-imidazole;

[0844]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-thiophen-3-ylI-1-isopropyl-4,5-dihydro-1H-imidazole;

[0845]1-{2-[3-Chloro-2-(2-naphthalen-1-yl-ethyl)-phenyl]-4,5-dihydro-imidazol-1-yl}-ethanone;

[0846]1-Benzyl-2-{2-[2-(5-bromo-2-methoxy-phenyl)-ethyl]-thiophen-3-yl}-4,5-dihydro-1H-imidazole;

[0847]3-(2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-thiophen-3-yl}-4,5-dihydro-imidazol-1-yl)-propionitrile;

[0848]3-(2-Naphthalen-1-yl-ethyl)-2-(1-propyl-4,5-dihydro-1H-imidazol-2-yl)-pyridine;

[0849]2-{2-[2-(2-Methoxy-naphthalen-1-yl)-ethyl]-phenyl}-3a,4,5,6,7,7a-hexahydro-1H-benzoimidazole;

[0850](2-{2-[2-(2-Methoxy-naphthalen-1-yl)-ethyl]-phenyl}-4,5-dihydro-imidazol-1-yl)-acetonitrile;

[0851]2-[3-Fluoro-2-(2-naphthalen-1-yl-ethyl)-phenyl]-4,5-dihydro-1H-imidazole;

[0852]2-(2-{2-[2-(tert-Butyl-dimethyl-silanyloxy)-naphthalen-1-yl]-ethyl}-3-fluoro-phenyl)-4,5-dihydro-1H-imidazole;

[0853]2-[2-(2-Benzofuran-7-yl-ethyl)-3-fluoro-phenyl]-4,5-dihydro-1H-imidazole;

[0854]1-(2,4-Bis-trifluoromethyl-benzyl)-2-{2-[2-(5-bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-1H-imidazole;

[0855]1-(3,5-Bis-trifluoromethyl-benzyl)-2-{2-[2-(5-bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}1-4,5-dihydro-1H-imidazole;

[0856]2-[3-Chloro-2-(2-naphthalen-1-yl-ethyl)-phenyl]-1-propyl-4,5-dihydro-1H-imidazole;

[0857]2-[3-Chloro-2-(2-naphthalen-1-yl-ethyl)-phenyl]-1-isopropyl-4,5-dihydro-1H-imidazole;

[0858]2-[3-Chloro-2-(2-naphthalen-1-yl-ethyl)-phenyl]-3a,4,5,6,7,7a-hexahydro-1H-benzoimidazole;

[0859]{2-[2-(2-Naphthalen-1-yl-ethyl)-phenyl]-4,5-dihydro-imidazol-1-yl}-acetonitrile;

[0860](2-{2-[2-(2-Methyl-naphthalen-1-yl)-ethyl]-phenyl}-4,5-dihydro-imidazol-1-yl)-acetonitrile;

[0861]{2-[3-Chloro-2-(2-naphthalen-1-yl-ethyl)-phenyl]-4,5-dihydro-imidazol-1-yl}-acetonitrile;

[0862]2-(3-Fluoro-2-{2-[2-(3-methyl-butoxy)-naphthalen-1-yl]-ethyl}-phenyl)-4,5-dihydro-1H-imidazole;

[0863]2-{2-[2-(2-Cyclohexylmethoxy-naphthalen-1-yl)-ethyl]-3-fluoro-phenyl}-4,5-dihydro-1H-imidazole;

[0864]2-(1-{2-[2-(4,5-Dihydro-1H-imidazol-2-yl)-6-fluoro-phenyl]-ethyl}-naphthalen-2-yloxy)-ethylamine;

[0865][2-(1-{2-[2-(4,5-Dihydro-1H-imidazol-2-yl)-6-fluoro-phenyl]-ethyl}-naphthalen-2-yloxy)-ethyl]-dimethyl-amine;

[0866]4-[2-(1-{2-[2-(4,5-Dihydro-1H-imidazol-2-yl)-6-fluoro-phenyl]-ethyl}-naphthalen-2-yloxy)-ethyl]-morpholine;

[0867][3-(1-{2-[2-(4,5-Dihydro-1H-imidazol-2-yl)-6-fluoro-phenyl]-ethyl}-naphthalen-2-yloxy)-propyl]-dimethyl-amine;

[0868]2-[2-(2-Benzo[b]thiophen-7-yl-ethyl)-3-fluoro-phenyl]-4,5-dihydro-1H-imidazole;

[0869]2-{2-[2-(2,5-Dimethyl-phenyl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[0870]2-{2-[2-(2,5-Dimethoxy-phenyl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[0871] 2-[2-(2-Benzofuran-7-yl-ethyl)-phenyl]-4,5-dihydro-1H-imidazole;

[0872]2-(2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-imidazol-1-yl)-propionitrile;

[0873]3-[2-(2-Naphthalen-1-yl-ethyl)-phenyl]-5,6,7,7a-tetrahydro-1H-pyrrolo[1,2-c]imidazole;

[0874]3-[3-Chloro-2-(2-naphthalen-1-yl-ethyl)-phenyl]-5,6,7,7a-tetrahydro-1H-pyrrolo[1,2-c]imidazole;

[0875]3-[2-(2-Naphthalen-1-yl-ethyl)-phenyl]-1,5,6,7,8,8a-hexahydro-imidazo[1,5-a]pyridine;

[0876]3-[3-Chloro-2-(2-naphthalen-1-yl-ethyl)-phenyl]-1,5,6,7,8,8a-hexahydro-imidazo[1,5-a]pyridine;

[0877]2-[2-(2-Benzo[1,3]dioxol-4-yl-ethyl)-3-fluoro-phenyl]-4,5-dihydro-1H-imidazole;

[0878]3-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-phenyl}-1,5,6,7,8,8a-hexahydro-imidazo[1,5-a]pyridine;

[0879]2-{2-[2-(5-Bromo-2,3-dihydro-benzofuran-7-y)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[0880]4,4,4-Trifluoro-3-{2-[2-(2-naphthalen-1-yl-ethyl)-phenyl]-4,5-dihydro-imidazol-1-yl}-butyronitrile;

[0881]3-(2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-imidazol-1-yl)-3-methoxy-propionitrile;

[0882]3-(2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-imidazol-1-yl)-butyronitrile;

[0883]3-{2-[2-(2-Naphthalen-1-yl-ethyl)-phenyl]-4,5-dihydro-imidazol-1-yl}-pentanenitrile;

[0884]3-(2-2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-imidazol-1-yl)-4,4,4-trifluoro-butyronitrile;

[0885]3-(2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-imidazol-1-yl)-pentanenitrile;

[0886]2-[2-(2-Benzo[1,3]dioxol-4-yl-ethyl)-3-chloro-phenyl]-4,5-dihydro-1H-imidazole;

[0887]2-[2-(2-Benzo[1,3]dioxol-4-yl-ethyl)-phenyl]-4,5-dihydro-1H-imidazole;

[0888]3-Methoxy-3-{2-[2-(2-naphthalen-1-yl-ethyl)-phenyl]-4,5-dihydro-imidazol-1-yl}-propionitrile;

[0889]3-[2-(2-Benzo[1,3]dioxol-4-yl-ethyl)-phenyl]-1,5,6,7,8,8a-hexahydro-imidazo[1,5-a]pyridine;

[0890]3-[2-(2-Benzo[1,3]dioxol-4-yl-ethyl)-phenyl]-5,6,7,7a-tetrahydro-1H-pyrrolo[1,2-c]imidazole;

[0891]3-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-phenyl}-1,5,6,7,8,8a-hexahydro-imidazo[1,5-a]pyridine;

[0892]3-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-phenyl}-5,6,7,7a-tetrahydro-1H-pyrrolo[1,2-c]imidazole;

[0893]2-{2-[2-(6-Bromo-benzo[1,3]dioxol-4-yl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[0894]2-{2-[2-(5-Bromo-2-cyclohexylmethoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-1H-imidazole;

[0895]2-{2-[2-(5-Bromo-benzofuran-7-yl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[0896][2-(4-Bromo-2-{2-[2-chloro-6-(4,5-dihydro-1H-imidazol-2-yl)-phenyl]-ethyl}-phenoxy)-ethyl]-dimethyl-amine;

[0897]2-(4-Bromo-2-{2-[2-chloro-6-(4,5-dihydro-1H-imidazol-2-yl)-phenyl]-ethyl}-phenoxy)-ethylamine;

[0898]2-{2-[2-(2-Bromo-5-fluoro-phenyl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[0899]2-{2-[2-(5-Bromo-2-fluoro-phenyl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[0900]2-[1-(2-Naphthalen-1-yl-ethyl)-pyrrolidin-2-yl]-4,5-dihydro-1H-imidazole;

[0901]2-{2-[2-(5-Chloro-2-fluoro-phenyl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[0902]2-{2-[2-(5-Bromo-2-chloro-phenyl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[0903]2-{2-[2-(2-Chloro-6-fluoro-phenyl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[0904] 2-[2-(2-Biphenyl-4-yl-ethyl)-phenyl]-4,5-dihydro-1H-imidazole;

[0905]2-{2-[2-(3,5-Dimethoxy-phenyl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[0906]2-[2-(2-Benzo[b]thiophen-4-yl-ethyl)-3-fluoro-phenyl]-4,5-dihydro-1H-imidazole;

[0907]2-[2-(2-Benzo[b]thiophen-6-yl-ethyl)-3-fluoro-phenyl]-4,5-dihydro-1H-imidazole;

[0908]2-{2-[2-(3-Methoxy-phenyl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[0909]2-{3-Chloro-2-[2-(2-methyl-naphthalen-1-yl)-ethyl]-phenyl}-3a,4,5,6,7,7a-hexahydro-1H-benzoimidazole;

[0910]2-{2-[2-(2,3-Dihydro-benzofuran-7-yl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[0911]2-{2-[2-(2-Bromo-5-methoxy-phenyl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[0912]2-{2-[2-(2,5-Difluoro-phenyl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[0913]2-{2-[2-(5-Bromo-benzofuran-7-yl)-ethyl]-3-fluoro-phenyl}-4,5-dihydro-1H-imidazole;

[0914]2-{2-[2-(5-Chloro-2-methoxy-phenyl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[0915]2-{2-[2-(5-Fluoro-2-methoxy-phenyl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[0916]2-{2-[2-(2,5-Dibromo-phenyl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[0917]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-phenyl}-4-isopropyl-1-methyl-4,5-dihydro-1H-imidazole;

[0918]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-phenyl}-5-ethyl-1-methyl-4,5-dihydro-1H-imidazole;

[0919]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-phenyl}-1,4-dimethyl-4,5-dihydro-1H-imidazole;

[0920]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-phenyl}-1-methyl-4,5-dihydro-1H-imidazole;

[0921]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-phenyl}-1-tert-butyl-4,5-dihydro-1H-imidazole;

[0922]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-phenyl}-1-butyl-4,5-dihydro-1H-imidazole;

[0923]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-phenyl}-1-isopropyl-4,5-dihydro-1H-imidazole;

[0924]1-[3-(2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-phenyl}-4,5-dihydro-imidazol-1-yl)-propyl]-4-methyl-piperazine;

[0925] 2-[2-(2-Naphthalen-2-yl-ethyl)-phenyl]-4,5-dihydro-1H-imidazole;

[0926]2-{2-[2-(5-Bromo-benzo[b]thiophen-7-yl)-ethyl]-3-fluoro-phenyl}-4,5-dihydro-1H-imidazole;

[0927] 8-{2-[2-(4,5-Dihydro-1H-imidazol-2-yl)-phenyl]-ethyl}-quinoline;

[0928]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-phenyl}-1-(2-fluoro-ethyl)-4,5-dihydro-1H-imidazole;

[0929]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-phenyl}-1-(2-pyrrolidin-1-yl-ethyl)-4,5-dihydro-1H-imidazole;

[0930]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-phenyl}-1-(3-pyrrolidin-1-yl-propyl)-4,5-dihydro-1H-imidazole;

[0931][3-(2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-phenyl}-4,5-dihydro-imidazol-1-yl)-propyl]-diethyl-amine;

[0932]4-[3-(2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-phenyl}-4,5-dihydro-imidazol-1-yl)-propyl]-morpholine;

[0933]2-{2-[2-(2,5-Dichloro-phenyl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[0934]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-phenyl}-1,5-dimethyl-4,5-dihydro-1H-imidazole;

[0935]2-{2-[2-(2-Bromo-5-chloro-phenyl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[0936]2-{2-[2-(2,5-Dibromo-phenyl)-ethyl]-3-fluoro-phenyl}-4,5-dihydro-1H-imidazole;

[0937]2-{2-[2-(2-Bromo-5-chloro-phenyl)-ethyl]-3-fluoro-phenyl}-4,5-dihydro-1H-imidazole;

[0938]2-{2-[2-(5-Bromo-2-chloro-phenyl)-ethyl]-3-fluoro-phenyl}-4,5-dihydro-1H-imidazole;

[0939] 2-{2-[2-(3-Bromo-phenyl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[0940]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-phenyl}-1-(2,2,2-trifluoro-ethyl)-4,5-dihydro-1H-imidazole;

[0941]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-phenyl}-1,4,5-trimethyl-4,5-dihydro-1H-imidazole;

[0942]5-Benzyloxymethyl-2-{2-[2-(5-bromo-2-methoxy-phenyl)-ethyl]-phenyl}-1-methyl-4,5-dihydro-1H-imidazole;

[0943]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-phenyl}-4-ethyl-1-methyl-4,5-dihydro-1H-imidazole;

[0944]2-{2-[2-(5-Bromo-2-methyl-benzofuran-7-yl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[0945]2-{2-[2-(6-Bromo-benzo[1,3]dioxol-4-yl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-1H-imidazole;

[0946]2-{2-[2-(6-Bromo-benzo[1,3]dioxol-4-yl)-ethyl]-3-fluoro-phenyl}-4,5-dihydro-1H-imidazole;

[0947]2-{2-[2-(5-Bromo-benzo[b]thiophen-7-yl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[0948]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-chloro-phenyl}-4,5-dihydro-1H-imidazole;

[0949]2-{2-[2-(5-Bromo-2,3-dimethyl-benzofuran-7-yl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[0950](2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-phenyl}-3-methyl-4,5-dihydro-3H-imidazol-4-yl)-methanol;

[0951]2-{2-[2-(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-ethyl]-3-fluoro-phenyl}-4,5-dihydro-1H-imidazole;

[0952]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-phenyl}-5,5-dimethyl-4,5-dihydro-1H-imidazole;

[0953]2-{2-[2-(2,3,5-Trichloro-phenyl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[0954]2-{2-[2-(3-Bromo-naphthalen-1-yl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[0955]2-{2-[2-(3-Bromo-naphthalen-1-yl)-ethyl]-3-fluoro-phenyl}-4,5-dihydro-1H-imidazole;

[0956]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-phenyl}-5-methyl-4,5-dihydro-1H-imidazole;

[0957]4-Chloro-3-{2-[2-(4,5-dihydro-1H-imidazol-2-yl)-6-fluoro-phenyl]-ethyl}-benzontrile;

[0958]2-{2-[2-(5-Bromo-2-trifluoromethoxy-phenyl)-ethyl]-3-fluoro-phenyl}-4,5-dihydro-1H-imidazole;

[0959]2-{2-[2-(5-Bromo-2-trifluoromethoxy-phenyl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[0960]2-{2-[2-(5-Bromo-2-trifluoromethoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-1H-imidazole;

[0961]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-methoxy-phenyl}-4,5-dihydro-1H-imidazole;

[0962]2-{2-[2-(5-Bromo-benzofuran-7-yl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-1H-imidazole;

[0963]2-{2-[2-(5-Bromo-2-difluoromethoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-1H-imidazole;

[0964]3-{2-[2-Chloro-6-(4,5-dihydro-1H-imidazol-2-yl)-phenyl]-ethyl}-4-methoxy-benzonitrile;

[0965]2-{2-[2-(5-Bromo-benzofuran-7-yl)-ethyl]-3-ethoxy-phenyl}-4,5-dihydro-1H-imidazole;

[0966]7-{2-[2-Chloro-6-(4,5-dihydro-1H-imidazol-2-yl)-phenyl]-ethyl}-benzofuran-5-carbonitrile;

[0967]2-{2-[2-(8-Bromo-naphthalen-1-yl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-1H-imidazole;

[0968]2-{3-Chloro-2-[2-(2-methyl-biphenyl-3-yl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[0969]2-[2-(2-Biphenyl-3-yl-ethyl)-3-chloro-phenyl]-4,5-dihydro-1H-imidazole;

[0970][4-(2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-imidazol-1-yl)-pentyl]-diethyl-amine;

[0971]2-{2-[2-(4-Bromo-4′-methoxy-biphenyl-2-yl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-1H-imidazole;

[0972]2-{2-[2-(4-Bromo-2′-methoxy-biphenyl-2-yl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-1H-imidazole;

[0973]2-{2-[2-(4-Bromo-3′-methoxy-biphenyl-2-yl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-1H-imidazole;

[0974]2-{2-[2-(6-Bromo-2-methoxy-naphthalen-1-yl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-1H-imidazole;

[0975]2-[2-(2-Biphenyl-2-yl-ethyl)-3-chloro-phenyl]-4,5-dihydro-1H-imidazole;

[0976]2-{3-Chloro-2-[2-(4-fluoro-naphthalen-1-yl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[0977]2-{2-[2-(4-Bromo-2′-chloro-biphenyl-2-yl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-1H-imidazole;

[0978]2-{2-[2-(4-Bromo-3′-chloro-biphenyl-2-yl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-1H-imidazole;

[0979]7-{2-[2-(4,5-Dihydro-1H-imidazol-2-yl)-6-fluoro-phenyl]-ethyl}-benzofuran-5-carbonitrile;

[0980]2-{2-[2-(4-Bromo-4′-chloro-biphenyl-2-yl)-ethyl]-3-chloro-phenyl}-4,5dihydro-1H-imidazole;

[0981]2-{2-[2-(2,5-Dibromo-benzofuran-7-yl)-ethyl]-3-fluoro-phenyl}-4,5-dihydro-1H-imidazole;

[0982]2-{3-Fluoro-2-[2-(2-methoxy-5-trifluoromethyl-phenyl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[0983]2-{3-Fluoro-2-[2-(5-phenyl-benzofuran-7-yl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[0984]2-{2-[2-(5-Ethynyl-benzofuran-7-yl)-ethyl]-3-fluoro-phenyl}-4,5-dihydro-1H-imidazole;

[0985]2-{3-Fluoro-2-[2-(5-methanesulfonyl-benzofuran-7-yl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[0986]2-{3-Fluoro-2-[2-(5-pyrrol-1-yl-benzofuran-7-yl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[0987]7-{2-[2-Fluoro-6-(1-isopropyl-4,5-dihydro-1H-imidazol-2-yl)-phenyl]-ethyl}-benzofuran-5-carbonitrile;

[0988]7-(2-{2-Fluoro-6-[1-(3-pyrrolidin-1-yl-propyl)-4,5-dihydro-1H-imidazol-2-yl]-phenyl}-ethyl)-benzofuran-5-carbonitrile;

[0989]7-{2-[2-Fluoro-6-(1-piperidin-4-ylmethyl-4,5-dihydro-1H-imidazol-2-yl)-phenyl]-ethyl}-benzofuran-5-carbonitrile;

[0990]4-(2-{2-[2-(5-Bromo-benzofuran-7-yl)-ethyl]-3-fluoro-phenyl}-4,5-dihydro-imidazol-1-ylmethyl)-piperidine;

[0991]2-{2-[2-(3-Bromo-naphthalen-1-yl)-ethyl]-3-fluoro-phenyl}-1-(3-pyrrolidin-1-yl-propyl)-4,5-dihydro-1H-imidazole;

[0992]2-{2-[2-(5-Bromo-benzofuran-7-yl)-ethyl]-3-fluoro-phenyl}-3a,4,5,6,7,7a-hexahydro-1H-benzoimidazole;

[0993]7-{2-[2-Fluoro-6-(3a,4,5,6,7,7a-hexahydro-1H-benzoimidazol-2-yl)-phenyl]-ethyl}-benzofuran-5-carbonitrile;

[0994]7-{2-[2-Chloro-6-(3a,4,5,6,7,7a-hexahydro-1H-benzoimidazol-2-yl)-phenyl]-ethyl}-benzofuran-5-carbonitrile;

[0995]2-{2-[2-(3-Bromo-naphthalen-1-yl)-ethyl]-3-chloro-phenyl}-3a,4,5,6,7,7a-hexahydro-1H-benzoimidazole;

[0996]2-{2-[2-(3-Bromo-naphthalen-1-yl)-ethyl]-3-fluoro-phenyl}-3a,4,5,6,7,7a-hexahydro-1H-benzoimidazole;

[0997]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-phenyl}-3a,4,5,6,7,7a-hexahydro-1H-benzoimidazole;

[0998]2-{2-[2-(5-Bromo-2,3-dimethyl-benzofuran-7-yl)-ethyl]-3-fluoro-phenyl}-1-(3-pyrrolidin-1-yl-propyl)-4,5-dihydro-1H-imidazole;

[0999]2-{2-[2-(5-Bromo-benzofuran-7-yl)-ethyl]-3-fluoro-phenyl}-1H-imidazole;

[1000]2-{2-[2-(5-Bromo-benzofuran-7-yl)-ethyl]-3-fluoro-phenyl}-1-isopropyl-1H-imidazole;

[1001]2-{2-[2-(5-Bromo-benzofuran-7-yl)-ethyl]-3-fluoro-phenyl}-1-(3-pyrrolidin-1-yl-propyl)-1H-imidazole;

[1002]2-{2-[2-(5-Bromo-3-phenyl-benzofuran-7-yl)-ethyl]-3-fluoro-phenyl}-4,5-dihydro-1H-imidazole;

[1003]2-{2-[2-(5-Bromo-3-isopropyl-benzofuran-7-yl)-ethyl]-3-fluoro-phenyl}-4,5-dihydro-1H-imidazole;

[1004]2-{2-[2-(5-Bromo-2,3-dimethyl-benzofuran-7-yl)-ethyl]-3-fluoro-phenyl}-4,5-dihydro-1H-imidazole;

[1005]2-{2-[2-(3-Bromo-naphthalen-1-yl)-ethyl]-3-fluoro-phenyl}-1-isopropyl-4,5-dihydro-1H-imidazole;

[1006]2-{2-[2-(5-Bromo-benzo[b]thiophen-7-yl)-ethyl]-3-fluoro-phenyl}-3a,4,5,6,7,7a-hexahydro-1H-benzoimidazole;

[1007]3-{2-[2-Fluoro-6-(3a,4,5,6,7,7a-hexahydro-1H-benzoimidazol-2-yl)-phenyl]-ethyl}-4-methoxy-benzonitrile;

[1008]2-{2-[2-(5-Bromo-benzo[b]thiophen-7-yl)-ethyl]-3-fluoro-phenyl}-1-(3-pyrrolidin-1-yl-propyl)-4,5-dihydro-1H-imidazole;

[1009]7-(2-{2-Fluoro-6-[1-(3-pyrrolidin-1-yl-propyl)-4,5-dihydro-1H-imidazol-2-yl]-phenyl}-ethyl)-benzo[b]thiophene-5-carbonitrile;

[1010]2-{2-[2-(5-Bromo-benzo[b]thiophen-7-yl)-ethyl]-3-chloro-phenyl}-3a,4,5,6,7,7a-hexahydro-1H-benzoimidazole;

[1011]3-{2-[2-Chloro-6-(3a,4,5,6,7,7a-hexahydro-1H-benzoimidazol-2-yl)-phenyl]-ethyl}-4-methoxy-benzonitrile;

[1012]2-{2-[2-(5-Bromo-benzo[b]thiophen-7-yl)-ethyl]-3-chloro-phenyl}-1-(3-pyrrolidin-1-yl-propyl)-4,5-dihydro-1H-imidazole;

[1013]7-(2-{2-Chloro-6-[1-(3-pyrrolidin-1-yl-propyl)-4,5-dihydro-1H-imidazol-2-yl]-phenyl}-ethyl)-benzo[b]thiophene-5-carbonitrile;

[1014]7-{2-[2-Chloro-6-(4,5-dihydro-1H-imidazol-2-yl)-phenyl]-ethyl}-benzo[b]thiophene-5-carbonitrile;

[1015]7-{2-[2-(4,5-Dihydro-1H-imidazol-2-yl)-6-fluoro-phenyl]-ethyl}-benzo[b]thiophene-5-carbonitrile,and pharmaceutically acceptable salts thereof.

[1016] Other compounds of the invention are shown in Table 4.

[1017] In one further embodiment, the methods of the invention do notinclude methods wherein2-[2-(2,5-dichlorothiophen-3-ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydropyrimidine(Compound A);2[2-(2-chloro-6-fluoro-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydropyrimidine(Compound B);1-(6-bromo-2-chloro-quinolin-4-yl)-3-(2-diethylaminoethyl)-urea(Compound AN);2-[2-(2,6-difluorobenzylsulfanyl)-phenyl]-1,4,5,6-tetrahydropyrimidine(Compound AO); 1-(4-hydroxy-1,3,5-trimethyl-piperadin-4-yl)-ethanone(Compound AR); 4,6-dimethyl-2-piperazin-1-yl-pyrimidine (Compound FP);2-piperazin-1-yl-pyrimidine (Compound FR); 1-pyridin-2-yl-piperazine(Compound FS); 2-piperazin-1-yl-4-trifluoromethyl pyrimidine (CompoundFT);6-piperazin-1-yl-7-trifluoromethyl-thieno[3,2-b]pyridine-3-carboxylicacid methyl ester (Compound FU); 5-bromo-2-piperazin-1-yl)-pyrimidine(Compound FV); 1-(3-trifluoromethyl-pyridin-2-yl)-piperazine (CompoundFW); 1-(5-trifluoromethyl-pyridin-2-yl)-piperazine (Compound FX);piperazine (Compound KY); or (2-Hexyloxy-phenyl)-carbamic acid2-piperidin-1-yl-1-piperidin-1-ylmethyl-ethyl ester (Compound OQ) areused as MC4-R binding compounds. In another further embodiment, thecompounds claimed as MC4-R binding compounds do not include those listedabove.

[1018] In another embodiment, the methods of the invention do notinclude methods wherein 2-naphthalen-1-ylmethyl-4,5-dihydro-1H-imidazole(NAPHAZOLINE; Compound AS);10-[2-(1-methyl-piperadin-2-yl)-ethyl]-2-methylsulfanyl-10H-phenothiazine(THORADIAZINE; THIODIAZINE; Compound AP);(2,6-dichloro-phenyl)-imidazolidin-2-ylidene-amine (CLONIDINE; CompoundAY); or 2-benzyl-4,5-dihydro-1H-imidazole (TOLAZOLINE; Compound AZ) areused as MC4-R binding compounds. In another further embodiment, theinvention pertain to compounds other than those listed above as MC4-Rbinding compounds.

[1019] In another further embodiment, the methods of the invention donot include5-(4-chloro-phenyl)-2,5-dihydro-3H-imidazo[2,1-a]-isoindol-5-ol(MASPINDOL; Compound DT) as an MC4-R binding compound. In oneembodiment, the compounds of the invention include MC4-R bindingcompounds other than MASPINDOL.

[1020] The term “alkyl” includes saturated aliphatic groups, includingstraight-chain alkyl groups (e.g., methyl, ethyl, propyl, butyl, pentyl,hexyl, heptyl, octyl, nonyl, decyl, etc.), branched-chain alkyl groups(isopropyl, tert-butyl, isobutyl, etc.), cycloalkyl (alicyclic) groups(cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), alkylsubstituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.The term alkyl further includes alkyl groups, which can further includeoxygen, nitrogen, sulfur or phosphorous atoms replacing one or morecarbons of the hydrocarbon backbone. In an embodiment, a straight chainor branched chain alkyl has 10 or fewer carbon atoms in its backbone(e.g., C₁-C₁₀ for straight chain, C₃-C₁₀ for branched chain), and morepreferably 6 or fewer. Likewise, preferred cycloalkyls have from 4-7carbon atoms in their ring structure, and more preferably have 5 or 6carbons in the ring structure.

[1021] Moreover, the term alkyl includes both “unsubstituted alkyls” and“substituted alkyls”, the latter of which refers to alkyl moietieshaving substituents replacing a hydrogen on one or more carbons of thehydrocarbon backbone. Such substituents can include, for example,alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate,phosphonato, phosphinato, cyano, amino (including alkyl amino,dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromaticor heteroaromatic moiety. Cycloalkyls can be further substituted, e.g.,with the substituents described above. An “alkylaryl” or an “aralkyl”moiety is an alkyl substituted with an aryl (e.g., phenylmethyl(benzyl)). The term “alkyl” also includes the side chains of natural andunnatural amino acids. Examples of halogenated alkyl groups includefluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,dichloromethyl, trichloromethyl, perfluoromethyl, perchloromethyl,perfluoroethyl, perchloroethyl, etc.

[1022] The term “aryl” includes groups, including 5-and 6-memberedsingle-ring aromatic groups that may include from zero to fourheteroatoms, for example, benzene, phenyl, pyrrole, furan, thiophene,thiazole, isothiaozole, imidazole, imidazoline, triazole, tetrazole,pyrazole, oxazole, isooxazole, pyridine, pyrazine, pyridazine, andpyrimidine, and the like. Furthermore, the term “aryl” includesmulticyclic aryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene,benzoxazole, benzodioxazole, benzothiazole, benzoimidazole,benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline,napthridine, indole, benzofuran, purine, benzofuran, deazapurine,isoindole, indan or indolizine. Those aryl groups having heteroatoms inthe ring structure may also be referred to as “aryl heterocycles”,“heterocycles,” “heteroaryls” or “heteroaromatics”. The aromatic ringcan be substituted at one or more ring positions with such substituentsas described above, as for example, halogen, hydroxyl, alkoxy,alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl,aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl,aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl,alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino(including alkyl amino, dialkylamino, arylamino, diarylamino, andalkylarylamino), acylamino (including alkylcarbonylamino,arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl,alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl,sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Arylgroups can also be fused or bridged with alicyclic or heterocyclic ringswhich are not aromatic so as to form a polycycle (e.g., tetralin).

[1023] The term “alkenyl” includes unsaturated aliphatic groupsanalogous in length and possible substitution to the alkyls describedabove, but that contain at least one double bond.

[1024] For example, the term “alkenyl” includes straight-chain alkenylgroups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl,octenyl, nonenyl, decenyl, etc.), branched-chain alkenyl groups,cycloalkenyl (alicyclic) groups (cyclopropenyl, cyclopentenyl,cyclohexenyl, cycloheptenyl, cyclooctenyl), alkyl or alkenyl substitutedcycloalkenyl groups, and cycloalkyl or cycloalkenyl substituted alkenylgroups. The term alkenyl further includes alkenyl groups which includeoxygen, nitrogen, sulfur or phosphorous atoms replacing one or morecarbons of the hydrocarbon backbone. In certain embodiments, a straightchain or branched chain alkenyl group has 6 or fewer carbon atoms in itsbackbone (e.g., C₂-C₆ for straight chain, C₃-C₆ for branched chain).Likewise, cycloalkenyl groups may have from 3-8 carbon atoms in theirring structure, and more preferably have 5 or 6 carbons in the ringstructure. The term C₂-C₆ includes alkenyl groups containing 2 to 6carbon atoms.

[1025] Moreover, the term alkenyl includes both “unsubstituted alkenyls”and “substituted alkenyls”, the latter of which refers to alkenylmoieties having substituents replacing a hydrogen on one or more carbonsof the hydrocarbon backbone. Such substituents can include, for example,alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl,phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino),acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyland ureido), amidino, imino, sulfhydryl, alkylthio, arylthio,thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl,sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl,alkylaryl, or an aromatic or heteroaromatic moiety.

[1026] The term “alkynyl” includes unsaturated aliphatic groupsanalogous in length and possible substitution to the alkyls describedabove, but which contain at least one triple bond.

[1027] For example, the term “alkynyl” includes straight-chain alkynylgroups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl,octynyl, nonynyl, decynyl, etc.), branched-chain alkynyl groups, andcycloalkyl or cycloalkenyl substituted alkynyl groups. The term alkynylfurther includes alkynyl groups which include oxygen, nitrogen, sulfuror phosphorous atoms replacing one or more carbons of the hydrocarbonbackbone. In certain embodiments, a straight chain or branched chainalkynyl group has 6 or fewer carbon atoms in its backbone (e.g., C₂-C₆for straight chain, C₃-C₆ for branched chain). The term C₂-C₆ includesalkynyl groups containing 2 to 6 carbon atoms.

[1028] Moreover, the term alkynyl includes both “unsubstituted alkynyls”and “substituted alkynyls”, the latter of which refers to alkynylmoieties having substituents replacing a hydrogen on one or more carbonsof the hydrocarbon backbone. Such substituents can include, for example,alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl,phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diaryl amino, and alkylaryl amino),acylamino (including alkylcarbonyl amino, arylcarbonylamino, carbamoyland ureido), amidino, imino, sulfhydryl, alkylthio, arylthio,thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl,sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl,alkylaryl, or an aromatic or heteroaromatic moiety.

[1029] Unless the number of carbons is otherwise specified, “loweralkyl” as used herein means an alkyl group, as defined above, but havingfrom one to five carbon atoms in its backbone structure. “Lower alkenyl”and “lower alkynyl” have chain lengths of, for example, 2-5 carbonatoms.

[1030] The term “acyl” includes compounds and moieties which contain theacyl radical (CH₃CO—) or a carbonyl group. The term “substituted acyl”includes acyl groups where one or more of the hydrogen atoms arereplaced by for example, alkyl groups, alkynyl groups, halogens,hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl,alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano,amino (including alkyl amino, dialkylamino, aryl amino, diarylamino, andalkylaryl amino), acylamino (including alkylcarbonylamino,arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl,alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl,sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[1031] The term “acylamino” includes moieties wherein an acyl moiety isbonded to an amino group. For example, the term includesalkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido groups.

[1032] The term “aroyl” includes compounds and moieties with an aryl orheteroaromatic moiety bound to a carbonyl group. Examples of aroylgroups include phenylcarboxy, naphthyl carboxy, etc.

[1033] The terms “alkoxyalkyl”, “alkylaminoalkyl” and “thioalkoxyalkyl”include alkyl groups, as described above, which further include oxygen,nitrogen or sulfur atoms replacing one or more carbons of thehydrocarbon backbone, e.g., oxygen, nitrogen or sulfur atoms.

[1034] The term “alkoxy” includes substituted and unsubstituted alkyl,alkenyl, and alkynyl groups covalently linked to an oxygen atom.Examples of alkoxy groups include methoxy, ethoxy, isopropyloxy,propoxy, butoxy, and pentoxy groups and may include cyclic groups suchas cyclopentoxy. Examples of substituted alkoxy groups includehalogenated alkoxy groups. The alkoxy groups can be substituted withgroups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl,phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino),acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyland ureido), amidino, imino, sulfhydryl, alkylthio, arylthio,thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl,sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl,alkylaryl, or an aromatic or heteroaromatic moieties. Examples ofhalogen substituted alkoxy groups include, but are not limited to,fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy,dichloromethoxy, trichloromethoxy, etc.

[1035] The term “amine” or “amino” includes compounds where a nitrogenatom is covalently bonded to at least one carbon or heteroatom such asalkyl aminos, alkenyl aminos, dialkyl aminos, aryl aminos, acyl aminos,etc. The term “alkyl amino” includes groups and compounds wherein thenitrogen is bound to at least one additional alkyl group and is includedin the term “amino.” The term “dialkyl amino” includes groups whereinthe nitrogen atom is bound to at least two additional alkyl groups andis included in the term “amino.” The term “arylamino” and “diarylamino”include groups wherein the nitrogen is bound to at least one or two arylgroups, respectively, and are included in the term “amino.” The term“alkylarylamino,” “alkylaminoaryl” or “arylaminoalkyl” refers to anamino group which is bound to at least one alkyl group and at least onearyl group. The term “alkaminoalkyl” refers to an alkyl, alkenyl, oralkynyl group bound to a nitrogen atom which is also bound to an alkylgroup and is included in the term “amino.”

[1036] The term “amide” or “aminocarboxy” includes compounds or moietieswhich contain a nitrogen atom which is bound to the carbon of a carbonylor a thiocarbonyl group. The term includes “alkaminocarboxy” groupswhich include alkyl, alkenyl, or alkynyl groups bound to an amino groupbound to a carboxy group. It includes arylaminocarboxy groups whichinclude aryl or heteroaryl moieties bound to an amino group which isbound to the carbon of a carbonyl or thiocarbonyl group. The terms“alkylaminocarboxy,” “alkenylaminocarboxy,” “alkynylaminocarboxy,” and“arylaminocarboxy” include moieties wherein alkyl, alkenyl, alkynyl andaryl moieties, respectively, are bound to a nitrogen atom which is inturn bound to the carbon of a carbonyl group.

[1037] The term “carbonyl” or “carboxy” includes compounds and moietieswhich contain a carbon connected with a double bond to an oxygen atom,and tautomeric forms thereof. Examples of moieties which contain acarbonyl include aldehydes, ketones, carboxylic acids, amides, esters,anhydrides, etc. The term “carboxy moiety” or “carbonyl moiety” refersto groups such as “alkylcarbonyl” groups wherein an alkyl group iscovalently bound to a carbonyl group, “alkenylcarbonyl” groups whereinan alkenyl group is covalently bound to a carbonyl group,“alkynylcarbonyl” groups wherein an alkynyl group is covalently bound toa carbonyl group, “arylcarbonyl” groups wherein an aryl group iscovalently attached to the carbonyl group. Furthermore, the term alsorefers to groups wherein one or more heteroatoms are covalently bondedto the carbonyl moiety. For example, the term includes moieties such as,for example, aminocarbonyl moieties, (wherein a nitrogen atom is boundto the carbon of the carbonyl group, e.g., an amide), aminocarbonyloxymoieties, wherein an oxygen and a nitrogen atom are both bond to thecarbon of the carbonyl group (e.g., also referred to as a “carbamate”).Furthermore, aminocarbonylamino groups (e.g., ureas) are also include aswell as other combinations of carbonyl groups bound to heteroatoms(e.g., nitrogen, oxygen, sulfur, etc. as well as carbon atoms).Furthermore, the heteroatom can be further substituted with one or morealkyl, alkenyl, alkynyl, aryl, aralkyl, acyl, etc. moieties.

[1038] The term “thiocarbonyl” or “thiocarboxy” includes compounds andmoieties which contain a carbon connected with a double bond to a sulfuratom. The term “thiocarbonyl moiety” includes moieties which areanalogous to carbonyl moieties. For example, “thiocarbonyl” moietiesinclude aminothiocarbonyl, wherein an amino group is bound to the carbonatom of the thiocarbonyl group, furthermore other thiocarbonyl moietiesinclude, oxythiocarbonyls (oxygen bound to the carbon atom),aminothiocarbonylamino groups, etc.

[1039] The term “ether” includes compounds or moieties which contain anoxygen bonded to two different carbon atoms or heteroatoms. For example,the term includes “alkoxyalkyl” which refers to an alkyl, alkenyl, oralkynyl group covalently bonded to an oxygen atom which is covalentlybonded to another alkyl group.

[1040] The term “ester” includes compounds and moieties which contain acarbon or a heteroatom bound to an oxygen atom which is bonded to thecarbon of a carbonyl group. The term “ester” includes alkoxycarboxygroups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,butoxycarbonyl, pentoxycarbonyl, etc. The alkyl, alkenyl, or alkynylgroups are as defined above.

[1041] The term “thioether” includes compounds and moieties whichcontain a sulfur atom bonded to two different carbon or hetero atoms.Examples of thioethers include, but are not limited to alkthioalkyls,alkthioalkenyls, and alkthioalkynyls. The term “alkthioalkyls” includecompounds with an alkyl, alkenyl, or alkynyl group bonded to a sulfuratom which is bonded to an alkyl group. Similarly, the term“alkthioalkenyls” and alkthioalkynyls” refer to compounds or moietieswherein an alkyl, alkenyl, or alkynyl group is bonded to a sulfur atomwhich is covalently bonded to an alkynyl group.

[1042] The term “thiol” includes groups with an —SH group. In certainembodiments, it may also include thioethers, thioalkyls, thioaryls,thiocarbonyls, as described above.

[1043] The term “hydroxy” or “hydroxyl” includes groups with an —OH or—O⁻.

[1044] The term “halogen” includes fluorine, bromine, chlorine, iodine,etc. The term “perhalogenated” generally refers to a moiety wherein allhydrogens are replaced by halogen atoms.

[1045] The terms “polycyclyl” or “polycyclic radical” include moietieswith two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls,aryls and/or heterocyclyls) in which two or more carbons are common totwo adjoining rings, e.g., the rings are “fused rings”. Rings that arejoined through non-adjacent atoms are termed “bridged” rings. Each ofthe rings of the polycycle can be substituted with such substituents asdescribed above, as for example, halogen, hydroxyl, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, alkoxycarbonyl, alkylaminoacarbonyl,aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl,aralkylcarbonyl, alkenylcarbonyl, aminocarbonyl, alkylthiocarbonyl,alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (includingalkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino),acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyland ureido), amidino, imino, sulfhydryl, alkylthio, arylthio,thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl,sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkyl,alkylaryl, or an aromatic or heteroaromatic moiety.

[1046] The term “heteroatom” includes atoms of any element other thancarbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfurand phosphorus.

[1047] The term “heterocycle” or “heterocyclic” includes saturated,unsaturated, aromatic (“heteroaryls” or “heteroaromatic”) and polycyclicrings which contain one or more heteroatoms. Examples of heterocyclesinclude, for example, benzodioxazole, benzofuran, benzoimidazole,benzothiazole, benzothiophene, benzoxazole, deazapurine, furan, indole,indolizine, imidazole, isooxazole, isoquinoline, isothiaozole,methylenedioxyphenyl, napthridine, oxazole, purine, pyrazine, pyrazole,pyridazine, pyridine, pyrimidine, pyrrole, quinoline, tetrazole,thiazole, thiophene, and triazole. Other heterocycles includemorpholine, piprazine, piperidine, thiomorpholine, and thioazolidine.The heterocycles may be substituted or unsubstituted. Examples ofsubstituents include, for example, halogen, hydroxyl, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, alkoxycarbonyl, alkylaminoacarbonyl,aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl,aralkylcarbonyl, alkenylcarbonyl, aminocarbonyl, alkylthiocarbonyl,alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (includingalkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino),acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyland ureido), amidino, imino, sulfhydryl, alkylthio, arylthio,thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl,sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkyl,alkylaryl, or an aromatic or heteroaromatic moiety.

[1048] It will be noted that the structure of some of the compounds ofthis invention includes asymmetric carbon atoms. It is to be understoodaccordingly that the isomers arising from such asymmetry (e.g., allenantiomers and diastereomers) are included within the scope of thisinvention, unless indicated otherwise. Such isomers can be obtained insubstantially pure form by classical separation techniques and bystereochemically controlled synthesis. Furthermore, the structures andother compounds and moieties discussed in this application also includeall tautomers thereof.

[1049] In a further embodiment, the compound is an antagonist of theMC4-R. In another embodiment, the compound is an agonist of the MC4-R.Compounds which are agonists of MC4-R can be identified using the cAMPassay given in Example 7.

[1050] The term “administering” includes routes of administration whichallow the MC4-R binding compound to perform its intended function, e.g.interacting with MC4-Rs and/or treating a MC4-R associated state.Examples of routes of administration which can be used include parentalinjection (e.g., subcutaneous, intravenous, and intramuscular),intraperitoneal injection, oral, inhalation, and transdermal. Theinjection can be bolus injections or can be continuous infusion.Depending on the route of administration, the MC4-R binding compound canbe coated with or disposed in a selected material to protect it fromnatural conditions which may detrimentally effect its ability to performits intended function. The MC4-R binding compound can be administeredalone or with a pharmaceutically acceptable carrier. Further, the MC4-Rbinding compound can be administered as a mixture of MC4-R bindingcompounds, which also can be coadministered with a pharmaceuticallyacceptable carrier. The MC4-R binding compound can be administered priorto the onset of a MC4-R associated state, or after the onset of a MC4-Rassociated state. The MC4-R binding compound also can be administered asa prodrug which is converted to another form in vivo.

[1051] In one embodiment of the invention, the invention includesmethods of treating an MC4-R associated state by administering the MC4-Rbinding compound of the invention in combination with art recognizedcompounds, e.g., therapeutic agents. For example, a patient sufferingfrom cachexia resulting from HIV, may be treated using both the MC4-Rbinding compounds of the invention in combination with art recognizedcompounds for treating the cachexia or HIV itself. The term “combinationwith” includes both simultaneous administration as well asadministration of the MC4-R binding compound before the art recognizedcompound or after the compound. The period between administrations ofthe MC4-R binding compound and the other agent may be any length of timewhich allows the compositions to perform their intended function, e.g.,the interval may be between few minutes, an hour, more than one hour,etc. In addition, the MC4-R binding compounds may also be administeredin combination with other MC4-R binding compounds of the invention.

[1052] The invention also features a pharmaceutical composition for thetreatment of a MC4-R associated state in a mammal. The pharmaceuticalcomposition includes a pharmaceutically acceptable carrier and aneffective amount of an MC4-R binding compound of the formula (I):

B-Z-E  (I)

[1053] wherein B is an anchor moiety, Z is a central moiety, and E is aMC4-R interacting moiety. In other embodiments, the pharmaceuticalcompositions of the invention include MC4-R binding compounds offormulae II, III, IV, V, VI, VII, VIII, IX, XVII, X, and/or XI.Pharmaceutical compositions comprising pharmaceutically acceptable saltsof at least one MC4-R binding compound are also included.

[1054] The language “effective amount” of the compound is that amountnecessary or sufficient to treat or prevent a MC4-R associated state,e.g. prevent the various morphological and somatic symptoms of a MC4-Rassociated state. The effective amount can vary depending on suchfactors as the size and weight of the subject, the type of illness, orthe particular MC4-R binding compound. For example, the choice of theMC4-R binding compound can affect what constitutes an “effectiveamount”. One of ordinary skill in the art would be able to study theaforementioned factors and make the determination regarding theeffective amount of the MC4-R binding compound without undueexperimentation. An in vivo assay as described in Example 6 below or anassay similar thereto (e.g., differing in choice of cell line or type ofillness) also can be used to determine an “effective amount” of a MC4-Rbinding compound. The ordinarily skilled artisan would select anappropriate amount of a MC4-R binding compound for use in theaforementioned in vivo assay. Advantageously, the effective amount iseffective to treat a disorder associated with pigmentation, bones (e.g.,osteoporosis, osteogenesis imperfecta (brittle bone disease),hypophosphatasia, Paget's disease, fibrous dysplasia, osteopetrosis,myeloma bone disease, bone formation, bone remodeling, bone healing, orthe depletion of calcium in bone, such as that which is related toprimary hyperparathyroidism) or feeding behavior and body weightdisorders or diseases associated with weight loss and wasting (e.g.,cachexia (e.g., chronic disease associated cachexia including cancercachexia, AIDS cachexia, CHF cachexia, etc.), anorexia, catabolicwasting, aging associated involuntary weight loss, and sarcopenia.

[1055] The regimen of administration can affect what constitutes aneffective amount. The MC4-R binding compound can be administered to thesubject either prior to or after the onset of a MC4-R associated state.Further, several divided dosages, as well as staggered dosages, can beadministered daily or sequentially, or the dose can be continuouslyinfused, or can be a bolus injection. Further, the dosages of the MC4-Rbinding compound(s) can be proportionally increased or decreased asindicated by the exigencies of the therapeutic or prophylacticsituation.

[1056] The term “treated,” “treating” or “treatment” includes thediminishment or alleviation of at least one symptom associated or causedby the state, disorder or disease being treated. For example, treatmentcan be diminishment of one or several symptoms of a disorder or completeeradication of a disorder.

[1057] The language “pharmaceutical composition” includes preparationssuitable for administration to mammals, e.g., humans. When the compoundsof the present invention are administered as pharmaceuticals to mammals,e.g., humans, they can be given per se or as a pharmaceuticalcomposition containing, for example, 0.1 to 99.5% (more preferably, 0.5to 90%) of active ingredient in combination with a pharmaceuticallyacceptable carrier.

[1058] The phrase “pharmaceutically acceptable carrier” is artrecognized and includes a pharmaceutically acceptable material,composition or vehicle, suitable for administering compounds of thepresent invention to mammals. The carriers include liquid or solidfiller, diluent, excipient, solvent or encapsulating material, involvedin carrying or transporting the subject agent from one organ, or portionof the body, to another organ, or portion of the body. Each carrier mustbe “acceptable” in the sense of being compatible with the otheringredients of the formulation and not injurious to the patient. Someexamples of materials which can serve as pharmaceutically acceptablecarriers include: sugars, such as lactose, glucose and sucrose;starches, such as corn starch and potato starch; cellulose, and itsderivatives, such as sodium carboxymethyl cellulose, ethyl cellulose andcellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients,such as cocoa butter and suppository waxes; oils, such as peanut oil,cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; glycols, such as propylene glycol; polyols, such asglycerin, sorbitol, mannitol and polyethylene glycol; esters, such asethyl oleate and ethyl laurate; agar; buffering agents, such asmagnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-freewater; isotonic saline; Ringer's solution; ethyl alcohol; phosphatebuffer solutions; and other non-toxic compatible substances employed inpharmaceutical formulations.

[1059] Wetting agents, emulsifiers and lubricants, such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releaseagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the compositions.

[1060] Examples of pharmaceutically acceptable antioxidants include:water soluble antioxidants, such as ascorbic acid, cysteinehydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfiteand the like; oil-soluble antioxidants, such as ascorbyl palmitate,butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT),lecithin, propyl gallate, α-tocopherol, and the like; and metalchelating agents, such as citric acid, ethylenediamine tetraacetic acid(EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[1061] Formulations of the present invention include those suitable fororal, nasal, topical, transdermal, buccal, sublingual, rectal, vaginaland/or parenteral administration. The formulations may conveniently bepresented in unit dosage form and may be prepared by any methods wellknown in the art of pharmacy. The amount of active ingredient which canbe combined with a carrier material to produce a single dosage form willgenerally be that amount of the compound which produces a therapeuticeffect. Generally, out of one hundred percent, this amount will rangefrom about 1 percent to about ninety-nine percent of active ingredient,preferably from about 5 percent to about 70 percent, most preferablyfrom about 10 percent to about 30 percent.

[1062] Methods of preparing these formulations or compositions includethe step of bringing into association a compound of the presentinvention with the carrier and, optionally, one or more accessoryingredients. In general, the formulations are prepared by uniformly andintimately bringing into association a compound of the present inventionwith liquid carriers, or finely divided solid carriers, or both, andthen, if necessary, shaping the product.

[1063] Formulations of the invention suitable for oral administrationmay be in the form of capsules, cachets, pills, tablets, lozenges (usinga flavored basis, usually sucrose and acacia or tragacanth), powders,granules, or as a solution or a suspension in an aqueous or non-aqueousliquid, or as an oil-in-water or water-in-oil liquid emulsion, or as anelixir or syrup, or as pastilles (using an inert base, such as gelatinand glycerin, or sucrose and acacia) and/or as mouth washes and thelike, each containing a predetermined amount of a compound of thepresent invention as an active ingredient. A compound of the presentinvention may also be administered as a bolus, electuary or paste.

[1064] In solid dosage forms of the invention for oral administration(capsules, tablets, pills, dragees, powders, granules and the like), theactive ingredient is mixed with one or more pharmaceutically acceptablecarriers, such as sodium citrate or dicalcium phosphate, and/or any ofthe following: fillers or extenders, such as starches, lactose, sucrose,glucose, mannitol, and/or silicic acid; binders, such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone,sucrose and/or acacia; humectants, such as glycerol; disintegratingagents, such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate; solutionretarding agents, such as paraffin; absorption accelerators, such asquaternary ammonium compounds; wetting agents, such as, for example,cetyl alcohol and glycerol monostearate; absorbents, such as kaolin andbentonite clay; lubricants, such a talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate, andmixtures thereof; and coloring agents. In the case of capsules, tabletsand pills, the pharmaceutical compositions may also comprise bufferingagents. Solid compositions of a similar type may also be employed asfillers in soft and hard-filled gelatin capsules using such excipientsas lactose or milk sugars, as well as high molecular weight polyethyleneglycols and the like.

[1065] A tablet may be made by compression or molding, optionally withone or more accessory ingredients. Compressed tablets may be preparedusing binder (for example, gelatin or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Molded tablets may be made bymolding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

[1066] The tablets, and other solid dosage forms of the pharmaceuticalcompositions of the present invention, such as dragees, capsules, pillsand granules, may optionally be scored or prepared with coatings andshells, such as enteric coatings and other coatings well known in thepharmaceutical-formulating art. They may also be formulated so as toprovide slow or controlled release of the active ingredient thereinusing, for example, hydroxypropylmethyl cellulose in varying proportionsto provide the desired release profile, other polymer matrices,liposomes and/or microspheres. They may be sterilized by, for example,filtration through a bacteria-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved in sterile water, or some other sterile injectable mediumimmediately before use. These compositions may also optionally containopacifying agents and may be of a composition that they release theactive ingredient(s) only, or preferentially, in a certain portion ofthe gastrointestinal tract, optionally, in a delayed manner. Examples ofembedding compositions which can be used include polymeric substancesand waxes. The active ingredient can also be in micro-encapsulated form,if appropriate, with one or more of the above-described excipients.

[1067] Liquid dosage forms for oral administration of the compounds ofthe invention include pharmaceutically acceptable emulsions,microemulsions, solutions, suspensions, syrups and elixirs. In additionto the active ingredient, the liquid dosage forms may contain inertdiluent commonly used in the art, such as, for example, water or othersolvents, solubilizing agents and emulsifiers, such as ethyl alcohol,isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol,benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (inparticular, cottonseed, groundnut, corn, germ, olive, castor and sesameoils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof.

[1068] Besides inert dilutents, the oral compositions can also includeadjuvants such as wetting agents, emulsifying and suspending agents,sweetening, flavoring, coloring, perfuming and preservative agents.

[1069] Suspensions, in addition to the active compounds, may containsuspending agents as, for example, ethoxylated isostearyl alcohols,polyoxyethylene sorbitol and sorbitan esters, microcrystallinecellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth,and mixtures thereof.

[1070] Formulations of the pharmaceutical compositions of the inventionfor rectal or vaginal administration may be presented as a suppository,which may be prepared by mixing one or more compounds of the inventionwith one or more suitable nonirritating excipients or carrierscomprising, for example, cocoa butter, polyethylene glycol, asuppository wax or a salicylate, and which is solid at room temperature,but liquid at body temperature and, therefore, will melt in the rectumor vaginal cavity and release the active compound.

[1071] Formulations of the present invention which are suitable forvaginal administration also include pessaries, tampons, creams, gels,pastes, foams or spray formulations containing such carriers as areknown in the art to be appropriate.

[1072] Dosage forms for the topical or transdermal administration of acompound of this invention include powders, sprays, ointments, pastes,creams, lotions, gels, solutions, patches and inhalants. The activecompound may be mixed under sterile conditions with a pharmaceuticallyacceptable carrier, and with any preservatives, buffers, or propellantswhich may be required.

[1073] The ointments, pastes, creams and gels may contain, in additionto an active compound of this invention, excipients, such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

[1074] Powders and sprays can contain, in addition to a compound of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants, suchas chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons,such as butane and propane.

[1075] Transdermal patches have the added advantage of providingcontrolled delivery of a compound of the present invention to the body.Such dosage forms can be made by dissolving or dispersing the compoundin the proper medium. Absorption enhancers can also be used to increasethe flux of the compound across the skin. The rate of such flux can becontrolled by either providing a rate controlling membrane or dispersingthe active compound in a polymer matrix or gel.

[1076] Ophthalmic formulations, eye ointments, powders, solutions andthe like, are also contemplated as being within the scope of thisinvention.

[1077] Pharmaceutical compositions of this invention suitable forparenteral administration comprise one or more compounds of theinvention in combination with one or more pharmaceutically acceptablesterile isotonic aqueous or nonaqueous solutions, dispersions,suspensions or emulsions, or sterile powders which may be reconstitutedinto sterile injectable solutions or dispersions just prior to use,which may contain antioxidants, buffers, bacteriostats, solutes whichrender the formulation isotonic with the blood of the intended recipientor suspending or thickening agents.

[1078] Examples of suitable aqueous and nonaqueous carriers which may beemployed in the pharmaceutical compositions of the invention includewater, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol, and the like), and suitable mixtures thereof,vegetable oils, such as olive oil, and injectable organic esters, suchas ethyl oleate. Proper fluidity can be maintained, for example, by theuse of coating materials, such as lecithin, by the maintenance of therequired particle size in the case of dispersions, and by the use ofsurfactants.

[1079] These compositions may also contain adjuvants such aspreservatives, wetting agents, emulsifying agents and dispersing agents.Prevention of the action of microorganisms may be ensured by theinclusion of various antibacterial and antifungal agents, for example,paraben, chlorobutanol, phenol sorbic acid, and the like. It may also bedesirable to include isotonic agents, such as sugars, sodium chloride,and the like into the compositions. In addition, prolonged absorption ofthe injectable pharmaceutical form may be brought about by the inclusionof agents which delay absorption such as aluminum monostearate andgelatin.

[1080] In some cases, in order to prolong the effect of a drug, it isdesirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This may be accomplished by the use of a liquidsuspension of crystalline or amorphous material having poor watersolubility. The rate of absorption of the drug then depends upon itsrate of dissolution which, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of aparenterally-administered drug form is accomplished by dissolving orsuspending the drug in an oil vehicle.

[1081] Injectable depot forms are made by forming microencapsulematrices of the subject compounds in biodegradable polymers such aspolylactide-polyglycolide. Depending on the ratio of drug to polymer,and the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions which are compatible with body tissue.

[1082] The preparations of the present invention may be given orally,parenterally, topically, or rectally. They are of course given by formssuitable for each administration route. For example, they areadministered in tablets or capsule form, by injection, inhalation, eyelotion, ointment, suppository, etc. administration by injection,infusion or inhalation; topical by lotion or ointment; and rectal bysuppositories. Oral administration is preferred.

[1083] The phrases “parenteral administration” and “administeredparenterally” as used herein means modes of administration other thanenteral and topical administration, usually by injection, and includes,without limitation, intravenous, intramuscular, intraarterial,intrathecal, intracapsular, intraorbital, intracardiac, intradermal,intraperitoneal, transtracheal, subcutaneous, subcuticular,intraarticular, subcapsular, subarachnoid, intraspinal and intrasternalinjection and infusion.

[1084] The phrases “systemic administration,” “administeredsystemically,” “peripheral administration” and “administeredperipherally” as used herein mean the administration of a compound, drugor other material other than directly into the central nervous system,such that it enters the patient's system and, thus, is subject tometabolism and other like processes, for example, subcutaneousadministration.

[1085] These compounds may be administered to humans and other animalsfor therapy by any suitable route of administration, including orally,nasally, as by, for example, a spray, rectally, intravaginally,parenterally, intracisternally and topically, as by powders, ointmentsor drops, including buccally and sublingually.

[1086] Regardless of the route of administration selected, the compoundsof the present invention, which may be used in a suitable hydrated form,and/or the pharmaceutical compositions of the present invention, areformulated into pharmaceutically acceptable dosage forms by conventionalmethods known to those of skill in the art.

[1087] Actual dosage levels of the active ingredients in thepharmaceutical compositions of this invention may be varied so as toobtain an amount of the active ingredient which is effective to achievethe desired therapeutic response for a particular patient, composition,and mode of administration, without being toxic to the patient.

[1088] The selected dosage level will depend upon a variety of factorsincluding the activity of the particular compound of the presentinvention employed, or the ester, salt or amide thereof, the route ofadministration, the time of administration, the rate of excretion of theparticular compound being employed, the duration of the treatment, otherdrugs, compounds and/or materials used in combination with theparticular compound employed, the age, sex, weight, condition, generalhealth and prior medical history of the patient being treated, and likefactors well known in the medical arts.

[1089] A physician or veterinarian having ordinary skill in the art canreadily determine and prescribe the effective amount of thepharmaceutical composition required. For example, the physician orveterinarian could start doses of the compounds of the inventionemployed in the pharmaceutical composition at levels lower than thatrequired in order to achieve the desired therapeutic effect andgradually increase the dosage until the desired effect is achieved.

[1090] In general, a suitable daily dose of a compound of the inventionwill be that amount of the compound which is the lowest dose effectiveto produce a therapeutic effect. Such an effective dose will generallydepend upon the factors described above. Generally, intravenous andsubcutaneous doses of the compounds of this invention for a patient,when used for the indicated analgesic effects, will range from about0.0001 to about 100 mg per kilogram of body weight per day, morepreferably from about 0.01 to about 50 mg per kg per day, and still morepreferably from about 1.0 to about 100 mg per kg per day. An effectiveamount is that amount treats an MC4-R associated state.

[1091] If desired, the effective daily dose of the active compound maybe administered as two, three, four, five, six or more sub-dosesadministered separately at appropriate intervals throughout the day,optionally, in unit dosage forms.

[1092] While it is possible for a compound of the present invention tobe administered alone, it is preferable to administer the compound as apharmaceutical composition.

[1093] As set out above, certain embodiments of the present compoundscan contain a basic functional group, such as amino or alkylamino, andare, thus, capable of forming pharmaceutically acceptable salts withpharmaceutically acceptable acids. The term “pharmaceutically acceptablesalts” is art recognized and includes relatively non-toxic, inorganicand organic acid addition salts of compounds of the present invention.These salts can be prepared in situ during the final isolation andpurification of the compounds of the invention, or by separatelyreacting a purified compound of the invention in its free base form witha suitable organic or inorganic acid, and isolating the salt thusformed. Representative salts include the hydrobromide, hydrochloride,sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate,palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate,citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate,glucoheptonate, lactobionate, and laurylsulphonate salts and the like.(See, e.g., Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci.66:1-19).

[1094] In other cases, the compounds of the present invention maycontain one or more acidic functional groups and, thus, are capable offorming pharmaceutically acceptable salts with pharmaceuticallyacceptable bases. The term “pharmaceutically acceptable salts” in theseinstances includes relatively non-toxic, inorganic and organic baseaddition salts of compounds of the present invention. These salts canlikewise be prepared in situ during the final isolation and purificationof the compounds, or by separately reacting the purified compound in itsfree acid form with a suitable base, such as the hydroxide, carbonate orbicarbonate of a pharmaceutically acceptable metal cation, with ammonia,or with a pharmaceutically acceptable organic primary, secondary ortertiary amine. Representative alkali or alkaline earth salts includethe lithium, sodium, potassium, calcium, magnesium, and aluminum saltsand the like. Representative organic amines useful for the formation ofbase addition salts include ethylamine, diethylamine, ethylenediamine,ethanolamine, diethanolamine, piperazine and the like.

[1095] The term “pharmaceutically acceptable esters” refers to therelatively non-toxic, esterified products of the compounds of thepresent invention. These esters can be prepared in situ during the finalisolation and purification of the compounds, or by separately reactingthe purified compound in its free acid form or hydroxyl with a suitableesterifying agent. Carboxylic acids can be converted into esters viatreatment with an alcohol in the presence of a catalyst. Hydroxyls canbe converted into esters via treatment with an esterifying agent such asalkanoyl halides. The term also includes lower hydrocarbon groupscapable of being solvated under physiological conditions, e.g., alkylesters, methyl, ethyl and propyl esters. (See, for example, Berge etal., supra.) A preferred ester group is an acetomethoxy ester group.Preferably, the amount of the MC4-R binding compound is effective totreat a pigmentation, bone, pain, or weight homeostasis disorder (e.g.,disorders or diseases associated with weight loss and wasting (e.g.,cachexia anorexia, catabolic wasting, aging associated involuntaryweight loss, sarcopenia).

[1096] The invention also pertains to packaged MC4-R binding compounds.The packaged MC4-R binding compounds include, an MC4-R binding compound(e.g., of formulae I, II, III, IV, V, VI, VII, VIII, IX, XVII, X, and/orXI), a container, and directions for using said MC4-R binding compoundto treat an MC4-R associated state, e.g., weight loss, etc.

[1097] Examples of MC4-R binding compounds for inclusion inpharmaceutical compositions include, for example,

[1098]2-[2-(4-benzyloxy-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1099]2-[2-(2-iodo-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1100]2-[2-(2-methoxy-5-nitro-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1101]2-[2-(naphthalen-1-ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1102]2-[2-(3-chloro-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1103]2-[2-(2,5-dimethoxy-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1104]2-[2-(3-bromo-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1105] 2-[2-(2-iodo-benzylsulfanyl)-phenyl]-4,5-dihydro-1H-imidazole;

[1106]2-[2-(2-methoxy-5-nitro-benzylsulfanyl)-phenyl]-4,5-dihydro-1H-imidazole;

[1107]2-[2-(2-methoxy-5-nitro-benzyloxy)-phenyl]-1,4,5,6-tetrahydropyrimidine;

[1108]2-[2-(2-bromo-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1109]2-[2-(3-iodo-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1110]2-[2-(2-methoxy-5-nitro-benzylsulfanyl)-phenyl]-3a,4,5,6,7,7a-hexahydro-1H-benzoimidazole;

[1111]2-{2-[2-(2-methoxy-naphthalen-1-yl)-ethyl]-phenyl}-1,4,5,6-tetrahydropyrimidine;

[1112]2-[2-(5-bromo-2-methoxy-benzylsulfanyl)-phenyl]-1,4,5,6,-tetrahydropyrimidine;

[1113]2-{2-[2-(2-methyl-naphthalen-1-yl)-ethyl]-phenyl}-1,4,5,6-tetrahydropyrimidine;

[1114]2-{2-[2-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-ethyl]-phenyl}-1,4,5,6-tetrahydropyrimidine;

[1115]2-[2-(2-methoxy-napthalen-1-ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydropyrimidine;

[1116] 2-(2-Benzylsulfanyl-phenyl)-1,4,5,6-tetrahydro-pyrimidine;

[1117] 2-(2-Pentadecylsulfanyl-phenyl)-1,4,5,6-tetrahydro-pyrimidine;

[1118]2-(2-Cyclohexylmethylsulfanyl-phenyl)-1,4,5,6-tetrahydro-pyrimidine;

[1119]2-[2-(2-Methyl-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1120]2-[2-(3-Nitro-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1121]2-[2-(3,5-Dimethoxy-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1122]2-[2-(4-Fluoro-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1123]2-[2-(2-Chloro-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1124]2-[2-(2-Fluoro-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1125]2-[2-(2,4-Bis-trifluoromethyl-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1126]2-[2-(3-Methoxy-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1127]2-[2-(3,5-Bis-trifluoromethyl-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1128]2-[2-(2-Methoxy-5-nitro-benzyloxy)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1129]2-[2-(2-Chloro-6-fluoro-benzylsulfanyl)-phenyl]-4,5-dihydro-1H-imidazole;

[1130] 2-(2-Benzylsulfanyl-phenyl)-4,5-dihydro-1H-imidazole;

[1131]2-[2-(2,6-Difluoro-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1132]2-[2-(Naphthalen-1-ylmethoxy)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1133]2-[2-(2-Methyl-naphthalen-1-ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1134]1-{2-[2-(2-Chloro-6-fluoro-benzylsulfanyl)-phenyl]-5,6-dihydro-4H-pyrmidin-1-yl}-ethanone;

[1135]2-[2-(2-Chloro-6-fluoro-benzylsulfanyl)-phenyl]-3a,4,5,6,7,7a-hexahydro-1H-benzoimidazole;

[1136]2-[2-(2-Iodo-benzylsulfanyl)-phenyl]-3a,4,5,6,7,7a-hexahydro-1H-benzoimidazole;

[1137]2-[2-(2,5-Dimethyl-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1138]4-[2-(1,4,5,6-Tetrahydro-pyrimidin-2-yl)-phenylsulfanylmethyl]-quinoline;

[1139]2-[2-(2-Methoxy-5-nitro-benzylsulfanyl)-pyridin-3-yl]-1,4,5,6-tetrahydro-pyrimidine;

[1140]2-[2-(2-Methoxy-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1141]2-[2-(2-Cyclopentyloxy-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1142]2-[2-(2,3-Dihydro-benzo[1,4]dioxin-5-ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1143]2-[2-(6-Methoxy-2,3-dihydro-benzo[1,4]dioxin-5-ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1144]2-[2-(5-fluoro-2-methoxy-benzylsulfanyl)-phenyl]-4,5-dihydro-1H-imidazole;

[1145]1-Methyl-2-[2-(naphthalen-1-ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1146]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-phenyl]-4,5-dihydro-1H-imidazole;

[1147]2-[2-(5-Bromo-2-methoxy-benzyloxy)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1148]2-[2-(Naphthalen-1-yloxymethyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1149]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-phenyl]-5,5-dimethyl-1,4,5,6-tetrahydro-pyrimidine;

[1150]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-phenyl]-5,5-dimethyl-4,5-dihydro-1H-imidazole;

[1151]2-[2-(2,6-Dimethoxy-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1152]2-[2-(2-Bromo-6-methoxy-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1153]2-[5-Bromo-2-(5-bromo-2-methoxy-benzylsulfanyl)-phenyl]-4,5-dihydro-1H-imidazole;

[1154]2-[5-Bromo-2-(5-bromo-2-methoxy-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1155]2-[4-Bromo-2-(5-bromo-2-methoxy-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1156]2-[2-(2-Bromo-5-methoxy-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1157]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-5-methyl-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1158]2-[2-(Biphenyl-3-ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1159]2-[2-(5-Chloro-2-methoxy-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1160]2-[2-(2-Methoxy-5-thiophen-3-yl-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1161]2-[2-(Biphenyl-2-ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1162]2-[2-(5-Iodo-2-methoxy-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1163]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-5-fluoro-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1164]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1165]2-[2-(4,4′-Dimethoxy-biphenyl-3-ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1166]2-[2-(9H-Fluoren-9-ylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1167]2-[2-(3′-Chloro-4′-fluoro-4-methoxy-biphenyl-3-ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1168]2-[2-(1-Naphthalen-1-yl-ethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1169]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-5-fluoro-phenyl]-4,5-dihydro-1H-imidazole;

[1170] 2-(2-Benzhydrylsulfanyl-phenyl)-1,4,5,6-tetrahydro-pyrimidine;

[1171]2-[2-(2′-Fluoro-4″-methoxy-[1,1′;4′,1″]terphenyl-3″-ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1172] 2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzamidine;

[1173]2-[4-(Naphthalen-1-ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1174]2-[2-(5-Ethynyl-2-methoxy-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1175]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-1,4,5,6-tetrahydro-pyrimidine;

[1176]2-[2-(5-Bromo-2-cyclopentyloxy-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1177]2-[2-(5-Bromo-2-ethoxy-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1178]2-[2-(5-Bromo-2-propoxy-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1179] [2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-diethyl-amine;

[1180] 1-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-piperazine;

[1181]C-{4-[3-(5-Bromo-2-methoxy-benzylsulfanyl)-quinoxalin-2-yl]-morpholin-2-yl}-methylamine;

[1182]2-[2-(2-Methoxy-5-methyl-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1183]2-[2-(5-Bromo-2-methoxy-benzyloxymethyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1184] [2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-dimethyl-amine;

[1185]2-[2-(5-Bromo-2-isopropoxy-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1186]2-[2-(2-Ethoxy-naphthalen-1-ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1187]2-[2-(2-Propoxy-naphthalen-1-ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1188]4-Methoxy-3-[2-(1,4,5,6-tetrahydro-pyrimidin-2-yl)-phenylsulfanylmethyl]-benzonitrile;

[1189]1-{4-Methoxy-3-[2-(1,4,5,6-tetrahydro-pyrimidin-2-yl)-phenylsulfanylmethyl]-phenyl}-ethanone;

[1190]2-[2-(Naphthalen-1-ylsulfanylmethyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1191] 1-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-piperidine;

[1192]C-{4-[2-(2-Methoxy-naphthalen-1-ylmethylsulfanyl)-benzyl]-morpholin-2-yl}-methylamine;

[1193]1-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-pyrrolidin-3-ylamine;

[1194]1-[2-(2-Methoxy-naphthalen-1-ylmethylsulfanyl)-benzyl]-pyrrolidin-3-ylamine;

[1195]3-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-1,5,6,7,8,8a-hexahydro-imidazo[1,5-a]pyridine;

[1196]3-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-5,6,7,7a-tetrahydro-1H-pyrrolo[1,2-c]imidazole;

[1197]2-[2-(Benzo[b]thiophen-3-ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1198]2-[3-Fluoro-2-(naphthalen-1-ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1199]2-(Naphthalen-1-ylmethylsulfanyl)-3-(1,4,5,6-tetrahydro-pyrimidin-2-yl)-phenylamine;

[1200]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1201]2-[2-(2-Methoxy-phenylsulfanylmethyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1202]1-{2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-phenyl]-5,6-dihydro-4H-pyrimidin-1-yl}-3-methyl-butan-1-one;

[1203]1-{2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-phenyl]-5,6-dihydro-4H-pyrimidin-1-yl}-2-phenyl-ethanone;

[1204]2-[3-(5-Bromo-2-methoxy-benzylsulfanyl)-pyridin-2-yl]-1,4,5,6-tetrahydro-pyrimidine;

[1205] N-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-phenyl]-guanidine;

[1206]2-[2-(2-Isopropoxy-naphthalen-1-ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1207]2-[2-(2-Cyclopentyloxy-naphthalen-1-ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1208](5-Bromo-2-methoxy-benzyl)-[2-(1,4,5,6-tetrahydro-pyrimidin-2-yl)-phenyl]-amine;

[1209]2-[2-(5-Bromo-2-methoxy-benzylsulfanylmethyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1210]2-[2-(2-Methoxy-naphthalen-1-ylsulfanylmethyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1211]2-[3-(5-Bromo-2-methoxy-benzylsulfanyl)-pyrazin-2-yl]-1,4,5,6-tetrahydro-pyrimidine;

[1212]2-[3-Chloro-2-(naphthalen-1-ylsulfanylmethyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1213]2-[2-(6-Bromo-2-methoxy-naphthalen-1-ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1214]2-[3-Chloro-2-(2-methoxy-naphthalen-1-ylsulfanylmethyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1215]2-[2-(5-Bromo-2-methoxy-phenylsulfanylmethyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1216]2-[2-(5-Bromo-2-methoxy-phenylsulfanylmethyl)-3-chloro-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1217]2-[1-(2-Naphthalen-1-yl-ethyl)-1H-pyrrol-2-yl]-1,4,5,6-tetrahydro-pyrimidine;

[1218](5-Bromo-2-methoxy-benzyl)-methyl-[2-(1,4,5,6-tetrahydro-pyrimidin-2-yl)-phenyl]-amine;

[1219] 2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzylamine;

[1220]2-[2-(2-Chloro-phenylsulfanylmethyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1221]2-[2-(2-Bromo-phenylsulfanylmethyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1222] 2-(2-o-Tolylsulfanylmethyl-phenyl)-1,4,5,6-tetrahydro-pyrimidine;

[1223]2-[2-(2,5-Dichloro-phenylsulfanylmethyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1224]2-(3-Amino-propylamino)-6-(5-bromo-2-methoxy-benzylsulfanyl)-benzonitrile;

[1225]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-1,4,5,6-tetrahydro-pyrimidine;

[1226] [2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-diethyl-amine;

[1227] 4-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-morpholine;

[1228]3′-(5-Bromo-2-methoxy-benzylsulfanyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl;

[1229]2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-piperazin-1-yl-6,7-dihydro-quinoxaline;

[1230] 1-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-piperidine;

[1231] C-{4-[2-(2-Methoxy-naphthalen-1-ylmethylsulfanyl)-benzyl]-morpholin-2-yl}-methylamine;

[1232]1-[3-(5-Bromo-2-methoxy-benzylsulfanyl)-pyrazin-2-yl]-pyrrolidin-3-ylamine;

[1233]1-[3-(5-Bromo-2-methoxy-benzylsulfanyl)-quinoxalin-2-yl]-pyrrolidin-3-ylamine;

[1234]1-[2-(2-Methoxy-naphthalen-1-ylmethylsulfanyl)-benzyl]-pyrrolidin-3-ylamine;

[1235]C-{4-[3-(5-Bromo-2-methoxy-benzylsulfanyl)-pyrazin-2-yl]-morpholin-3-yl}-methylamine;

[1236] 1-[3-Fluoro-2-(2-naphthalen-1-yl-ethyl)-benzyl]-piperazine;

[1237]1-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzyl]-azetidine;

[1238]1-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzyl]-pyrrolidin-3-ol;

[1239] [2-(Naphthalen-1-ylmethylsulfanyl)-phenyl]-carbamic acid1-aza-bicyclo[2.2.2]oct-3-yl ester;

[1240] [2-(2-Methyl-naphthalen-1-ylmethylsulfanyl)-phenyl]-carbamic acid1-aza-bicyclo[2.2.2]oct-3-yl ester;

[1241] [2-(2-Methyl-naphthalen-1-ylmethylsulfanyl)-phenyl]-carbamic acid2-piperidin-1-yl-ethyl ester;

[1242]{1-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzyl]-pyrrolidin-2-yl}-methanol;

[1243]4-tert-Butyl-N-naphthalen-1-ylmethyl-N-(2-piperidin-1-yl-ethyl)-benzamide;

[1244]N,N-Dimethyl-N′-naphthalen-2-ylmethyl-N′-naphthalen-1-ylmethyl-propane-1,3-diamine;

[1245]N-(5-Bromo-2-methoxy-benzyl)-N′,N′-dimethyl-N-naphthalen-1-ylmethyl-propane-1,3-diamine;

[1246] 1-Naphthalen-1-ylmethyl-3-phenethyl-l-(2-piperidin-1-yl-ethyl)-thiourea;

[1247]3-(4-Dimethylamino-phenyl)-1-(3-dimethylamino-propyl)-1-naphthalen-1-ylmethyl-thiourea;

[1248]4-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzylamino]-piperidine-1-carboxylicacid ethyl ester;

[1249] 2-[2-(2-Naphthalen-1-yl-ethyl)-phenyl]-ethylamine;

[1250] Naphthalene-2-sulfonic acid(2-dimethylamino-ethyl)-naphthalen-1-ylmethyl-amide;

[1251]1-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzyl]-2-methoxymethyl-pyrrolidine;

[1252] (2-Hexyloxy-phenyl)-carbamic acid2-piperidin-1-yl-1-piperidin-1-ylmethyl-ethyl ester;

[1253] 3-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyloxy]-pyrrolidine;

[1254]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyloxymethyl]-pyrrolidine;

[1255] 2-[2-(Naphthalen-1-ylsulfanylmethyl)-phenyl]-piperidine;

[1256] 3-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzylamino]-propan-1-ol;

[1257]3-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzylamino]-3-methyl-butan-1-ol;

[1258] 1-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-pyrrolidin-3-ol;

[1259]{1-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-pyrrolidin-2-yl}-methanol;

[1260]{1-[2-(Naphthalen-1-ylsulfanylmethyl)-benzyl]-piperidin-2-yl}-methanol;

[1261]2-[2-(Naphthalen-1-ylsulfanylmethyl)-pyrrolidin-1-yl]-ethyl-N-pyrrolidine;

[1262]N-pyrrolyl-[1-(2-naphthalen-1-yl-ethyl)-pyrrolidin-2-ylmethyl]-amine;

[1263] 1-(2-Naphthalen-1-yl-ethyl)-piperidine-2-carboxylic acid methylester;

[1264](3-Bromo-benzyl)-(1-ethyl-pyrrolidin-2-ylmethyl)-naphthalen-1-ylmethyl-amine;

[1265] 3-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyloxy]-piperidine;

[1266](5-Bromo-2-methoxy-benzyl)-(1-ethyl-pyrrolidin-2-ylmethyl)-naphthalen-1-ylmethyl-amine;

[1267](1-Ethyl-pyrrolidin-2-ylmethyl)-naphthalen-2-ylmethyl-naphthalen-1-ylmethyl-amine;

[1268]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyloxymethyl]-pyrrolidine;

[1269](3-Bromo-benzyl)-(3-imidazol-1-yl-propyl)-naphthalen-1-ylmethyl-amine;

[1270](3-Imidazol-1-yl-propyl)-naphthalen-2-ylmethyl-naphthalen-1-ylmethyl-amine;

[1271] [2-(Naphthalen 1-ylmethylsulfanyl)-phenyl]-carbamic acid2-pipenidin-1-yl-1-piperidin-1-ylmethyl-ethyl ester;

[1272] [2-(Naphthalen-1-ylmethylsulfanyl)-phenyl]-carbamic acid2-dimethylamino-ethyl ester;

[1273] 1-[2-(Naphthalen-1-ylsulfanylmethyl)-benzyl]-piperazine;

[1274][3-(2-Methyl-piperidin-1-yl)-propyl]-[2-(naphthalen-1-ylsulfanylmethyl)-benzyl]-amine;

[1275] 1-[3-Chloro-2-(naphthalen-1-ylsulfanylmethyl)-benzyl]-piperazine;

[1276]N,N-Dimethyl-N′-(2-naphthalen-1-yl-ethyl)-N′-naphthalen-1-ylmethyl-ethane-1,2-diamine;

[1277]{1-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzyl]-piperidin-2-yl}-methanol;

[1278] 1-[2-(2-Naphthalen-1-yl-ethyl)-benzyl]-piperazine;

[1279][3-(2-Methyl-piperidin-1-yl)-propyl]-[2-(2-naphthalen-1-yl-ethyl)-benzyl]-amine;

[1280] 1-[3-Fluoro-2-(2-naphthalen-1-yl-ethyl)-benzyl]-piperazine;

[1281]{1-[3-Chloro-2-(naphthalen-1-ylsulfanylmethyl)-benzyl]-piperidin-2-yl}-methanol;

[1282]{1-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzyl]-piperidin-2-yl}-methanol;

[1283] {1-[2-(2-Naphthalen-1-yl-ethyl)-benzyl]-piperidin-2-yl}-methanol;

[1284][3-(2-Methyl-piperidin-1-yl)-propyl]-[2-(2-naphthalen-1-yl-ethyl)-benzyl]-amine;

[1285] 1-[2-(2-Naphthalen-1-yl-ethyl)-benzyl]-pyrrolidin-3-ylamine;

[1286]1-Phenyl-3-piperazin-1-yl-5,6,7,8-tetrahydro-isoquinoline-4-carbonitrile;

[1287] 2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-phenyl]-6-ethyl-1,4,5,6-tetrahydro-pyrimidine;

[1288]2-[2-(4-Methoxy-biphenyl-3-ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1289]2-[2-(2-Methoxy-5-phenylethynyl-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1290]2-[2-(2-Naphthalen-1-yl-ethyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1291]2-[3-(2-Methoxy-naphthalen-1-ylsulfanylmethyl)-thiophen-2-yl]-1,4,5,6-tetrahydro-pyrimidine;

[1292]2-[2-(2,5-Dimethoxy-phenylsulfanylmethyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1293]2-[2-(4-Methyl-naphthalen-1-ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1294]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-4,4-dimethyl-4,5-dihydro-1H-imidazole;

[1295]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-5,5-dimethyl-1,4,5,6-tetrahydro-pyrimidine;

[1296]2-[3-(Naphthalen-1-ylsulfanylmethyl)-thiophen-2-yl]-1,4,5,6-tetrahydro-pyrimidine;

[1297]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-phenyl}-1,4,5,6-tetrahydro-pyrimidine;

[1298]2-[3-Chloro-2-(2-naphthalen-1-yl-ethyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1299]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-phenyl}-1,4,5,6-tetrahydro-pyrimidine;

[1300]2-[2-(5-Bromo-2-methoxy-phenylsulfanylmethyl)-3-fluoro-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1301]2-[2-(Naphthalen-1-ylsulfanylmethyl)-phenyl]-4,5-dihydro-1H-imidazole;

[1302]2-[3-Fluoro-2-(naphthalen-1-ylsulfanylmethyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1303]2-[3-Bromo-2-(naphthalen-1-ylsulfanylmethyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1304]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-1,4,5,6-tetrahydro-pyrimidine;

[1305]2-[2-(2-Methoxy-5-trifluoromethyl-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1306]2-[4-(Naphthalen-1-ylsulfanylmethyl)-thiophen-3-yl]-1,4,5,6-tetrahydro-pyrimidine;

[1307]2-[2-(Naphthalen-1-ylsulfanylmethyl)-thiophen-3-yl]-1,4,5,6-tetrahydro-pyrimidine;

[1308]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-trifluoromethyl-phenyl}-1,4,5,6-tetrahydro-pyrimidine;

[1309]2-[2-(2-Naphthalen-1-yl-ethyl)-3-trifluoromethyl-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1310]2-[2-(6-Fluoro-naphthalen-1-ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1311]{1-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-piperidin-2-yl}-methanol;

[1312]2-[3-Fluoro-2-(2-naphthalen-1-yl-ethyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1313][2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzyl]-[3-(2-methyl-piperidin-1-yl)-propyl]-amine;

[1314]1-[2-(-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzyl]-pyrrolidin-3-ylamine;

[1315]1-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzyl]-piperazine;

[1316]5,5-Dimethyl-2-[2-(2-naphthalen-1-yl-ethyl)-phenyl]-4,5-dihydro-1H-imidazole;

[1317]2-[3-Fluoro-2-(2-naphthalen-1-yl-ethyl)-phenyl]-5,5-dimethyl-4,5-dihydro-1H-imidazole;

[1318]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3,5-difluoro-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1319]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3,5-difluoro-phenyl]-5,5-dimethyl-4,5-dihydro-1H-imidazole;

[1320]3-(2-Naphthalen-1-yl-ethyl)-2-(1,4,5,6-tetrahydro-pyrimidin-2-yl)-phenylamine;

[1321] Amino-[2-(2-naphthalen-1-yl-ethyl)-phenyl]-acetonitrile;

[1322] 1-[2-(2-Naphthalen-1-yl-ethyl)-phenyl]-ethane-1,2-diamine;

[1323]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-phenyl]-4-methyl-4,5-dihydro-1H-imidazole;

[1324]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-4-methyl-4,5-dihydro-1H-imidazole;

[1325]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-phenyl]-4-methyl-4,5-dihydro-1H-imidazole;

[1326]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3,4-difluoro-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1327]2-[3-Fluoro-2-(naphthalen-1-ylsulfanylmethyl)-phenyl]-5,5-dimethyl-4,5-dihydro-1H-imidazole;

[1328]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-1-methyl-ethyl]-phenyl}-1,4,5,6-tetrahydro-pyrimidine;

[1329] 2-[2-(5-Bromo-2-methoxy benzylsulfanyl)-3-fluoro-4-trifluoromethyl-phenyl]-4,4-dimethyl-4,5-dihydro-1H-imidazole;

[1330] 2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-4-trifluoromethyl-phenyl]-5,5-dimethyl-1,4,5,6-tetrahydro-pyrimidine;

[1331]2-[3-Methoxy-2-(2-naphthalen-1-yl-ethyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1332]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-phenyl]-1,4,5,6-tetrahydro-pyrimidin-5-ol;

[1333]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-methoxy-phenyl}-1,4,5,6-tetrahydro-pyrimidine;

[1334]1-Amino-3-[2-(5-bromo-2-methoxy-phenyl)-7-chloro-benzo[b]thiophen-3-ylamino]-propan-2-ol;

[1335]2-[2-(1-Methyl-2-naphthalen-1-yl-ethyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1336]3-(5-Bromo-2-methoxy-benzylsulfanyl)-2-fluoro-4-(1,4,5,6-tetrahydro-pyrimidin-2-yl)-phenylamine;

[1337]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-methyl-phenyl}-1,4,5,6-tetrahydro-pyrimidine;

[1338]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-1,4,5,6-tetrahydro-pyrimidin-5-ol;

[1339]1-Amino-3-[2-(5-bromo-2-methoxy-phenyl)-7-fluoro-benzo[b]thiophen-3-ylamino]-propan-2-ol;

[1340] 2-[3-Methoxy-2-(naphthalen-1-ylsulfanylmethyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1341]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-1,4,5,6-tetrahydro-pyrimidin-5-ol;

[1342]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-5-methoxy-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1343]2-{2-[2-Chloro-6-(1,4,5,6-tetrahydro-pyrimidin-2-yl)-phenyl]-ethyl}-phenol;

[1344]2-[3-Methoxy-2-(naphthalen-1-ylsulfanylmethyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidin-5-ol;

[1345]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-methyl-phenyl}-5-methyl-4,5dihydro-1H-imidazole;

[1346]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-methyl-phenyl}-1,4,5,6-tetrahydro-pyrimidin-5-ol;

[1347]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3,4-difluoro-phenyl]-1,4,5,6-tetrahydro-pyrimidin-5-ol;

[1348]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,4-dimethyl-4,5-dihydro-1H-imidazole;

[1349]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-4-methyl-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1350]4,4-Dimethyl-2-[2-(naphthalen-1-ylmethylsulfanyl)-phenyl]-4,5-dihydro-oxazole;

[1351]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-4-methoxy-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1352]2-[5-(5-Bromo-2-methoxy-benzyl)-2-methyl-thiophen-3-yl]-1,4,5,6-tetrahydro-pyrmidine;

[1353]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-thiophen-3-yl}-1,4,5,6-tetrahydro-pyrimidine;

[1354]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-ethoxy-phenyl}-1,4,5,6-tetrahydro-pyrmidine;

[1355]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-isopropoxy-phenyl}-1,4,5,6-tetrahydro-pyrimidine;

[1356]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-4-methoxy-phenyl}-1,4,5,6-tetrahydro-pyrimidine;

[1357]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-isopropoxy-phenyl}-1,4,5,6-tetrahydro-pyrimidin-5-ol;

[1358]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-methoxy-phenyl}-1,4,5,6-tetrahydro-pyrimidin-5-ol;

[1359]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-4-methoxy-phenyl}-1,4,5,6-tetrahydro-pyrimidine;

[1360]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-ethoxy-phenyl}-1,4,5,6-tetrahydro-pyrimidin-5-ol;

[1361]2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-(1,4,5,6-tetrahydro-pyrimidin-2-yl)-benzonitrile;

[1362]2-{3-Benzyloxy-2-[2-(5-bromo-2-methoxy-phenyl)-ethyl]-phenyl}-1,4,5,6-tetrahydro-pyrimidine;

[1363]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-4-butyl-phenyl}-1,4,5,6-tetrahydro-pyrimidine;

[1364]2-{5-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-1,4,5,6-tetrahydro-pyrimidine;

[1365]2-{5-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-8-chloro-2,3-dihydro-benzo[1,4]dioxin-6-yl}-1,4,5,6-tetrahydro-pyrimidine;

[1366]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-ethyl-phenyl}-1,4,5,6-tetrahydro-pyrimidine;

[1367]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-propyl-phenyl}-1,4,5,6-tetrahydro-pyrimidine;

[1368]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-butoxy-phenyl}-1,4,5,6-tetrahydro-pyrimidine;

[1369]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-isobutoxy-phenyl}-1,4,5,6-tetrahydro-pyrimidine;

[1370]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-butoxy-phenyl}-1,4,5,6-tetrahydro-pyrimidin-5-ol;

[1371]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-5-methoxy-1,4,5,6-tetrahydro-pyrimidine;

[1372]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-1-methyl-1,4,5,6-tetrahydro-pyrimidine;

[1373]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-1-methyl-4,5-dihydro-1H-imidazole;

[1374][2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-1-methyl-4,5-dihydro-1H-imidazole;

[1375]2-{2-[3-(1,4,5,6-Tetrahydro-pyrimidin-2-yl)-biphenyl-2-yl]-ethyl}-phenol;

[1376]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-1-methyl-4,5-dihydro-1H-imidazole;

[1377]N-(3-Amino-propyl)-2-[2-(5-bromo-2-methoxy-phenyl)-ethyl]-6-methoxy-benzamide;

[1378]N-(3-Amino-propyl)-2-[2-(5-bromo-2-methoxy-phenyl)-ethyl]-6-methyl-benzamide;

[1379]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-5,6-dihydro-4H-pyrimidine-1-carboxylicacid 1-acetoxy-2-methyl-propyl ester;

[1380]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-5,6-dihydro-4H-pyrimidine-1-carboxylicacid 1-acetoxy-ethyl ester;

[1381]3-(5-Bromo-2-methoxy-phenyl)-5-chloro-3,4-dihydro-isoquinolin-1-ylamine;

[1382]2-[2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-(4-methoxy-benzyloxy)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;

[1383]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-5-methyl-1,4,5,6-tetrahydro-pyrimidin-5-ol;

[1384]2-[(5-Bromo-2-methoxy-phenyl)-(3-piperidin-1-yl-propylamino)-methyl]-3-chloro-6-methyl-phenol;

[1385]1-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-methyl-benzyl}-piperazine;

[1386]1-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-methyl-benzyl}-4-methyl-piperazine;

[1387]1-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-methyl-benzyl}-piperidine;

[1388]{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-methyl-benzyl}-diethyl-amine;

[1389] 3-(5-Bromo-2-methoxy-phenyl)-1,2,3,4-tetrahydro-isoquinoline;

[1390]1-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-benzyl}-piperazine;

[1391]1-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-benzyl}-4-methyl-piperazine;

[1392]1-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-benzyl}-piperidine;

[1393]{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-benzyl}-diethyl-amine;

[1394]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-1H-imidazole;

[1395](1-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-benzyl}-piperidin-2-yl)-methanol;

[1396]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-propoxy-phenyl}-1,4,5,6-tetrahydro-pyrimidine;

[1397]1-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-4-methyl-piperazine;

[1398]1-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-chloro-benzyl}-piperazine;

[1399]1-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-chloro-benzyl}-4-methyl-piperazine;

[1400]1-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-chloro-benzyl}-piperidine;

[1401]{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-chloro-benzyl}-diethyl-amine;

[1402]1-(5-Bromo-2-methoxy-benzyl)-2-(4-methoxy-benzyl)-2,3-dihydro-1H-isoindole;

[1403]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-5,6-dihydro-4H-pyrimidine-1-carboxylicacid 1-acetoxy-ethyl ester;

[1404]1-(2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}1-5,6-dihydro-4H-pyrimidin-1-yl)-ethanone;

[1405]1-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-benzyl}-4-methyl-piperazine;

[1406]{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-benzyl}-diethyl-amine;

[1407]1-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-benzyl}-piperidine;

[1408](1-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-benzyl}-piperidin-2-yl)-methanol;

[1409]4-Fluoro-N-{2-[4-(2-methoxy-phenyl)-piperazin-1-yl]-ethyl}-N-pyridin-2-yl-benzamide;

[1410]3-(5-Bromo-2-methoxy-phenyl)-2-methyl-1,2,3,4-tetrahydro-isoquinoline;

[1411]1-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-benzyl}-piperazine;

[1412]1-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-benzyl}-4-methyl-piperazine;

[1413]1-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-benzyl}-piperidine;

[1414]{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-benzyl}-diethyl-amine;

[1415]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-1H-imidazole;

[1416](1-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-benzyl}-piperidin-2-yl)-methanol;

[1417]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-propoxy-phenyl}-1,4,5,6-tetrahydro-pyrimidine;

[1418]1-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-benzyl]-4-methyl-piperazine;

[1419]1-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-chloro-benzyl}-piperazine;

[1420]1-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-chloro-benzyl}-4-methyl-piperazine;

[1421]1-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-chloro-benzyl}-piperidine;

[1422]{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-chloro-benzyl}-diethyl-amine;

[1423]1-(5-Bromo-2-methoxy-benzyl)-2-(4-methoxy-benzyl)-2,3-dihydro-1H-isoindole;

[1424]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-5,6-dihydro-4H-pyrimidine-1-carboxylicacid 1-acetoxy-ethyl ester;

[1425]1-(2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-5,6-dihydro-4H-pyrimidin-1-yl)-ethanone;

[1426]1-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-benzyl}-4-methyl-piperazine;

[1427]{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-benzyl}-diethyl-amine;

[1428]1-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-benzyl}-piperidine;

[1429]4-Fluoro-N-{2-[4-(2-methoxy-phenyl)-piperazin-1-yl]-ethyl}-N-pyridin-2-yl-benzamide;

[1430]3-(5-Bromo-2-methoxy-phenyl)-2-methyl-1,2,3,4-tetrahydro-isoquinoline;

[1431]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-1-ethyl-4,5-dihydro-1H-imidazole;

[1432]{2-[3-(5-Bromo-2-methoxy-phenyl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-diethyl-amine;

[1433]1-(2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-imidazol-1-yl)-ethanone;

[1434]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-imidazole-1-carboxylicacid ethyl ester;

[1435]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-imidazole-1-carboxylicacid isobutyl ester;

[1436]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-imidazole-1-carboxylicacid tert-butyl ester;

[1437]1-(2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-imidazol-1-yl)-2,2-dimethyl-propan-1-one;

[1438] 1-(5-Bromo-2-methoxy-benzyl)-2,3-dihydro-1H-isoindole;

[1439] 1-(2-Methoxy-benzyl)-2-methyl-2,3-dihydro-1H-isoindole;

[1440] 2-Methyl-1-naphthalen-1-ylmethyl-2,3-dihydro-1H-isoindole;

[1441]1-{2-[3-Chloro-2-(2-naphthalen-1-yl-ethyl)-phenyl]-4,5-dihydro-imidazol-1-yl}-2,2-dimethyl-propan-1-one;

[1442]{2-[1-(5-Bromo-2-methoxy-benzyl)-1,3-dihydro-isoindol-2-yl]-ethyl}-diethyl-amine;

[1443]2-[3-Chloro-2-(2-naphthalen-1-yl-ethyl)-phenyl]-1-methyl-1,4,5,6-tetrahydro-pyrimidine;

[1444]2-[3-Chloro-2-(2-naphthalen-1-yl-ethyl)-phenyl]-5,6-dihydro-4H-pyrimidine-1-carboxylicacid tert-butyl ester;

[1445]2-[3-Chloro-2-(2-naphthalen-1-yl-ethyl)-phenyl]-4,5-dihydro-1H-imidazole;

[1446]1-{2-[3-Chloro-2-(2-naphthalen-1-yl-ethyl)-phenyl]-4,5-dihydro-imidazol-1-yl}-ethanone;

[1447]2-[3-Chloro-2-(2-naphthalen-1-yl-ethyl)-phenyl]-4,5-dihydro-imidazole-1-carboxylicacid isobutyl ester;

[1448]2-[3-Chloro-2-(2-naphthalen-1-yl-ethyl)-phenyl]-4,5-dihydro-imidazole-1-carboxylicacid tert-butyl ester;

[1449]2-[3-Chloro-2-(2-naphthalen-1-yl-ethyl)-phenyl]-4,5-dihydro-imidazole-1-carboxylicacid ethyl ester;

[1450]2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-N-(3-formylamino-propyl)-6-methyl-benzamide;

[1451]2-[3-Chloro-2-(2-naphthalen-1-yl-ethyl)-phenyl]-1-ethyl-4,5-dihydro-1H-imidazole;

[1452]1-(2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-5,6-dihydro-4H-pyrimidin-1-yl)-2,2-dimethyl-propan-1-one;

[1453]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-thiophen-3-yl}-4,5-dihydro-1H-imidazole;

[1454]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-5,6-dihydro-4H-pyrimidine-1-carboxylicacid isobutyl ester;

[1455]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-1-isocyanomethyl-4,5-dihydro-1H-imidazole;

[1456]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-thiophen-3-yl}-1-methyl-4,5-dihydro-1H-imidazole;

[1457]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-thiophen-3-yl}-1-ethyl-4,5-dihydro-1H-imidazole;

[1458] 3-(5-Bromo-2-methoxy-benzyl)-2-methyl-2,3-dihydro-isoindol-1-one;

[1459]4-(2-Methoxy-benzyl)-2-(4-methoxy-benzyl)-1,2,3,4-tetrahydro-isoquinoline;

[1460]4-(5-Bromo-2-methoxy-benzyl)-2-(4-methoxy-benzyl)-1,2,3,4-tetrahydro-isoquinoline;

[1461]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-1-propyl-4,5-dihydro-1H-imidazole;

[1462]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-3a,4,5,6,7,7a-hexahydro-1H-benzoimidazole;

[1463]5,5-Dimethyl-2-[2-(naphthalen-1-ylsulfanylmethyl)-phenyl]-4,5-dihydro-1H-imidazole;

[1464]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-phenyl]-4,4-dimethyl-4,5-dihydro-1H-imidazole;

[1465]N-(5-Bromo-2-methoxy-benzyl)-N′-methyl-N-naphthalen-1-ylmethyl-ethane-1,2-diamine;

[1466]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-1-ethyl-1,4,5,6-tetrahydro-pyrimidine;

[1467]2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-N,N,N′-trimethyl-benzamidine;

[1468]2-[3-Chloro-2-(2-naphthalen-1-yl-ethyl)-phenyl]-1-methyl-4,5-dihydro-1H-imidazole;

[1469]1-Benzyl-2-{2-[2-(5-bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-1H-imidazole;

[1470]({2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-pyrrolidin-1-yl-methylene)-methyl-amine;

[1471]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-1-isopropyl-4,5-dihydro-1H-imidazole;

[1472]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-1-(2,2,2-trifluoro-ethyl)-4,5-dihydro-1H-imidazole;

[1473]2-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-phenyl]-6-ethyl-1,4,5,6-tetrahydro-pyrimidine;

[1474]2-(2-Benzylsulfanyl-phenyl)-3a,4,5,6,7,7a-hexahydro-1H-benzoimidazole;

[1475]2-[2-(2-Chloro-6-fluoro-benzylsulfanyl)-phenyl]-3a,4,5,6,7,7a-hexahydro-1H-benzoimidazole;

[1476]2-[2-(2-Iodo-benzylsulfanyl)-phenyl]-3a,4,5,6,7,7a-hexahydro-1H-benzoimidazole;

[1477] 2-[2-(2-Methoxy-5-nitro-benzyl sulfanyl)-phenyl]-3a,4,5,6,7,7a-hexahydro-1H-benzoimidazole;

[1478]3-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-fluoro-phenyl]-1,5,6,7,8,8a-hexahydro-imidazo[1,5-a]pyridine;

[1479]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-phenyl}-4,5-dihydro-1H-imidazole;

[1480]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-ethoxy-phenyl}-1-ethyl-4,5-dihydro-1H-imidazole;

[1481]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-ethoxy-phenyl}-4,5-dihydro-1H-imidazole;

[1482]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-ethoxy-phenyl}-1-methyl-4,5-dihydro-1H-imidazole;

[1483]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-methoxy-phenyl}-1-methyl-4,5-dihydro-1H-imidazole;

[1484]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-phenyl}-1-ethyl-4,5-dihydro-1H-imidazole;

[1485] 2-[2-(2-Naphthalen-1-yl-ethyl)-phenyl]-4,5-dihydro-1H-imidazole;

[1486]1-Ethyl-2-[2-(2-naphthalen-1-yl-ethyl)-phenyl]-4,5-dihydro-1H-imidazole;

[1487]1-Methyl-2-[2-(2-naphthalen-1-yl-ethyl)-phenyl]-4,5-dihydro-1H-imidazole;

[1488]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-phenyl}-1-ethyl-4,5-dihydro-1H-imidazole;

[1489]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[1490]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-methyl-phenyl}-4,5-dihydro-1H-imidazole;

[1491]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-phenyl}-1-methyl-4,5-dihydro-1H-imidazole;

[1492]3-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-5,6-dihydro-imidazo[2,1-b]thiazole;

[1493]1-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-2-(4,4-dimethyl-4,5-dihydro-1H-imidazol-2-ylsulfanyl)-ethanone;

[1494]3-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-6,6-dimethyl-5,6-dihydro-imnidazo[2,1-b]thiazole;

[1495]{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-benzyl}-(4,5-dihydro-1H-imidazol-2-yl)-amine;

[1496]{3-Chloro-2-[2-(2-methoxy-phenyl)-ethyl]-benzyl}-(4,5-dihydro-1H-imidazol-2-yl)-amine;

[1497](2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-imidazol-1-yl)-aceticacid;

[1498](2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-3a,4,5,6,7,7a-hexahydro-benzoimidazol-1-yl)-acetonitrile;

[1499]3-(2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-imidazol-1-yl)-propionitrile;

[1500] 2-(3-Fluoro-2-phenethyl-phenyl)-4,5-dihydro-1H-imidazole;

[1501]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-1-propyl-3a,4,5,6,7,7a-hexahydro-1H-benzoimidazole;

[1502]3-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-1,5,6,7,8,8a-hexahydro-imidazo[1,5-a]pyridine;

[1503]3-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-5,6,7,7a-tetrahydro-1H-pyrrolo[1,2-c]imidazole;

[1504]3-(2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-imidazol-1-yl)-2-methyl-propionitrile;

[1505]2-{2-[2-(2-Methyl-naphthalen-1-yl)-ethyl]-phenyl}-3a,4,5,6,7,7a-hexahydro-1H-benzoimidazole;

[1506]2-{2-[2-(2-Methyl-naphthalen-1-yl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[1507]2-[2-(2-Naphthalen-1-yl-ethyl)-phenyl]-3a,4,5,6,7,7a-hexahydro-1H-benzoimidazole;

[1508]2-{2-[2-(2-Methoxy-naphthalen-1-yl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[1509]2-(1-Isopropyl-4,5-dihydro-1H-imidazol-2-yl)-3-(2-naphthalen-1-yl-ethyl)-pyridine;

[1510]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-thiophen-3-yl}-1-propyl-4,5-dihydro-1H-imidazole;

[1511]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-thiophen-3-yl}-1-isopropyl-4,5-dihydro-1H-imidazole;

[1512]1-{2-[3-Chloro-2-(2-naphthalen-1-yl-ethyl)-phenyl]-4,5-dihydro-imidazol-1-yl}-ethanone;

[1513]1-Benzyl-2-{2-[2-(5-bromo-2-methoxy-phenyl)-ethyl]-thiophen-3-yl}-4,5-dihydro-1H-imidazole;

[1514]3-(2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-thiophen-3-yl}-4,5-dihydro-imidazol-1-yl)-propionitrile;

[1515]3-(2-Naphthalen-1-yl-ethyl)-2-(1-propyl-4,5-dihydro-1H-imidazol-2-yl)-pyridine;

[1516]2-{2-[2-(2-Methoxy-naphthalen-1-yl)-ethyl]-phenyl}-3a,4,5,6,7,7a-hexahydro-1H-benzoimidazole;

[1517](2-{2-[2-(2-Methoxy-naphthalen-1-yl)-ethyl]-phenyl}-4,5-dihydro-imidazol-1-yl)-acetonitrile;

[1518]2-[3-Fluoro-2-(2-naphthalen-1-yl-ethyl)-phenyl]-4,5-dihydro-1H-imidazole;

[1519]2-(2-{2-[2-(tert-Butyl-dimethyl-silanyloxy)-naphthalen-1-yl]-ethyl}-3-fluoro-phenyl)-4,5-dihydro-1H-imidazole;

[1520]2-[2-(2-Benzofuran-7-yl-ethyl)-3-fluoro-phenyl]-4,5-dihydro-1H-imidazole;

[1521]1-(2,4-Bis-trifluoromethyl-benzyl)-2-{2-[2-(5-bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-1H-imidazole;

[1522]1-(3,5-Bis-trifluoromethyl-benzyl)-2-{2-[2-(5-bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}1-4,5-dihydro-1H-imidazole;

[1523]2-[3-Chloro-2-(2-naphthalen-1-yl-ethyl)-phenyl]-1-propyl-4,5-dihydro-1H-imidazole;

[1524]2-[3-Chloro-2-(2-naphthalen-1-yl-ethyl)-phenyl]-1-isopropyl-4,5-dihydro-1H-imidazole;

[1525]2-[3-Chloro-2-(2-naphthalen-1-yl-ethyl)-phenyl]-3a,4,5,6,7,7a-hexahydro-1H-benzoimidazole;

[1526]{2-[2-(2-Naphthalen-1-yl-ethyl)-phenyl]-4,5-dihydro-imidazol-1-yl}-acetonitrile;

[1527](2-{2-[2-(2-Methyl-naphthalen-1-yl)-ethyl]-phenyl}-4,5-dihydro-imidazol-1-yl)-acetonitrile;

[1528]{2-[3-Chloro-2-(2-naphthalen-1-yl-ethyl)-phenyl]-4,5-dihydro-imidazol-1-yl}-acetonitrile;

[1529]2-(3-Fluoro-2-{2-[2-(3-methyl-butoxy)-naphthalen-1-yl]-ethyl}-phenyl)-4,5-dihydro-1H-imidazole;

[1530]2-{2-[2-(2-Cyclohexylmethoxy-naphthalen-1-yl)-ethyl]-3-fluoro-phenyl}-4,5-dihydro-1H-imidazole;

[1531]2-(1-{2-[2-(4,5-Dihydro-1H-imidazol-2-yl)-6-fluoro-phenyl]-ethyl}-naphthalen-2-yloxy)-ethylamine;

[1532][2-(1-{2-[2-(4,5-Dihydro-1H-imidazol-2-yl)-6-fluoro-phenyl]-ethyl}-naphthalen-2-yloxy)-ethyl]-dimethyl-amine;

[1533]4-[2-(1-{2-[2-(4,5-Dihydro-1H-imidazol-2-yl)-6-fluoro-phenyl]-ethyl}-naphthalen-2-yloxy)-ethyl]-morpholine;

[1534][3-(1-{2-[2-(4,5-Dihydro-1H-imidazol-2-yl)-6-fluoro-phenyl]-ethyl}-naphthalen-2-yloxy)-propyl]-dimethyl-amine;

[1535]2-[2-(2-Benzo[b]thiophen-7-yl-ethyl)-3-fluoro-phenyl]-4,5-dihydro-1H-imidazole;

[1536]2-{2-[2-(2,5-Dimethyl-phenyl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[1537]2-{2-[2-(2,5-Dimethoxy-phenyl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[1538] 2-[2-(2-Benzofuran-7-yl-ethyl)-phenyl]-4,5-dihydro-1H-imidazole;

[1539]2-(2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-imidazol-1-yl)-propionitrile;

[1540]3-[2-(2-Naphthalen-1-yl-ethyl)-phenyl]-5,6,7,7a-tetrahydro-1H-pyrrolo[1,2-c]imidazole;

[1541]3-[3-Chloro-2-(2-naphthalen-1-yl-ethyl)-phenyl]-5,6,7,7a-tetrahydro-1H-pyrrolo[1,2-c]imidazole;

[1542]3-[2-(2-Naphthalen-1-yl-ethyl)-phenyl]-1,5,6,7,8,8a-hexahydro-imidazo[1,5-a]pyridine;

[1543]3-[3-Chloro-2-(2-naphthalen-1-yl-ethyl)-phenyl]-1,5,6,7,8,8a-hexahydro-imidazo[1,5-a]pyridine;

[1544]2-[2-(2-Benzo[1,3]dioxol-4-yl-ethyl)-3-fluoro-phenyl]-4,5-dihydro-1H-imidazole;

[1545]3-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-phenyl}-1,5,6,7,8,8a-hexahydro-imidazo[1,5-a]pyridine;

[1546]2-{2-[2-(5-Bromo-2,3-dihydro-benzofuran-7-y)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[1547]4,4,4-Trifluoro-3-{2-[2-(2-naphthalen-1-yl-ethyl)-phenyl]-4,5-dihydro-imidazol-1-yl}-butyronitrile;

[1548]3-(2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-imidazol-1-yl)-3-methoxy-propionitrile;

[1549]3-(2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-imidazol-1-yl)-butyronitrile;

[1550]3-{2-[2-(2-Naphthalen-1-yl-ethyl)-phenyl]-4,5-dihydro-imidazol-1-yl}-pentanenitrile;

[1551]3-(2-2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-imidazol-1-yl)-4,4,4-trifluoro-butyronitrile;

[1552]3-(2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-imidazol-1-yl)-pentanenitrile;

[1553]2-[2-(2-Benzo[1,3]dioxol-4-yl-ethyl)-3-chloro-phenyl]-4,5-dihydro-1H-imidazole;

[1554]2-[2-(2-Benzo[1,3]dioxol-4-yl-ethyl)-phenyl]-4,5-dihydro-1H-imidazole;

[1555]3-Methoxy-3-{2-[2-(2-naphthalen-1-yl-ethyl)-phenyl]-4,5-dihydro-imidazol-1-yl}-propionitrile;

[1556]3-[2-(2-Benzo[1,3]dioxol-4-yl-ethyl)-phenyl]-1,5,6,7,8,8a-hexahydro-imidazo[1,5-a]pyridine;

[1557]3-[2-(2-Benzo[1,3]dioxol-4-yl-ethyl)-phenyl]-5,6,7,7a-tetrahydro-1H-pyrrolo[1,2-c]imidazole;

[1558]3-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-phenyl}-1,5,6,7,8,8a-hexahydro-imidazo[1,5-a]pyridine;

[1559]3-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-phenyl}-5,6,7,7a-tetrahydro-1H-pyrrolo[1,2-c]imidazole;

[1560]2-{2-[2-(6-Bromo-benzo[1,3]dioxol-4-yl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[1561]2-{2-[2-(5-Bromo-2-cyclohexylmethoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-1H-imidazole;

[1562]2-{2-[2-(5-Bromo-benzofuran-7-yl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[1563][2-(4-Bromo-2-{2-[2-chloro-6-(4,5-dihydro-1H-imidazol-2-yl)-phenyl]-ethyl}-phenoxy)-ethyl]-dimethyl-amine;

[1564]2-(4-Bromo-2-{2-[2-chloro-6-(4,5-dihydro-1H-imidazol-2-yl)-phenyl]-ethyl}-phenoxy)-ethylamine;

[1565]2-{2-[2-(2-Bromo-5-fluoro-phenyl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[1566]2-{2-[2-(5-Bromo-2-fluoro-phenyl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[1567]2-[1-(2-Naphthalen-1-yl-ethyl)-pyrrolidin-2-yl]-4,5-dihydro-1H-imidazole;

[1568]2-{2-[2-(5-Chloro-2-fluoro-phenyl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[1569]2-{2-[2-(5-Bromo-2-chloro-phenyl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[1570]2-{2-[2-(2-Chloro-6-fluoro-phenyl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[1571] 2-[2-(2-Biphenyl-4-yl-ethyl)-phenyl]-4,5-dihydro-1H-imidazole;

[1572]2-{2-[2-(3,5-Dimethoxy-phenyl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[1573]2-[2-(2-Benzo[b]thiophen-4-yl-ethyl)-3-fluoro-phenyl]-4,5-dihydro-1H-imidazole;

[1574]2-[2-(2-Benzo[b]thiophen-6-yl-ethyl)-3-fluoro-phenyl]-4,5-dihydro-1H-imidazole;

[1575]2-{2-[2-(3-Methoxy-phenyl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[1576]2-{3-Chloro-2-[2-(2-methyl-naphthalen-1-yl)-ethyl]-phenyl}-3a,4,5,6,7,7a-hexahydro-1H-benzoimidazole;

[1577]2-{2-[2-(2,3-Dihydro-benzofuran-7-yl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[1578]2-{2-[2-(2-Bromo-5-methoxy-phenyl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[1579]2-{2-[2-(2,5-Difluoro-phenyl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[1580]2-{2-[2-(5-Bromo-benzofuran-7-yl)-ethyl]-3-fluoro-phenyl}-4,5-dihydro-1H-imidazole;

[1581]2-{2-[2-(5-Chloro-2-methoxy-phenyl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[1582]2-{2-[2-(5-Fluoro-2-methoxy-phenyl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[1583]2-{2-[2-(2,5-Dibromo-phenyl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[1584]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-phenyl}-4-isopropyl-1-methyl-4,5-dihydro-1H-imidazole;

[1585]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-phenyl}-5-ethyl-1-methyl-4,5-dihydro-1H-imidazole;

[1586]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-phenyl}-1,4-dimethyl-4,5-dihydro-1H-imidazole;

[1587]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-phenyl}-1-methyl-4,5-dihydro-1H-imidazole;

[1588]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-phenyl}-1-tert-butyl-4,5-dihydro-1H-imidazole;

[1589]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-phenyl}-1-butyl-4,5-dihydro-1H-imidazole;

[1590]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-phenyl}-1-isopropyl-4,5-dihydro-1H-imidazole;

[1591]1-[3-(2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-phenyl}-4,5-dihydro-imidazol-1-yl)-propyl]-4-methyl-piperazine;

[1592] 2-[2-(2-Naphthalen-2-yl-ethyl)-phenyl]-4,5-dihydro-1H-imidazole;

[1593]2-{2-[2-(5-Bromo-benzo[b]thiophen-7-yl)-ethyl]-3-fluoro-phenyl}-4,5-dihydro-1H-imidazole;

[1594] 8-{2-[2-(4,5-Dihydro-1H-imidazol-2-yl)-phenyl]-ethyl}-quinoline;

[1595]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-phenyl}-1-(2-fluoro-ethyl)-4,5-dihydro-1H-imidazole;

[1596]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-phenyl}-1-(2-pyrrolidin-1-yl-ethyl)-4,5-dihydro-1H-imidazole;

[1597]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-phenyl}-1-(3-pyrrolidin-1-yl-propyl)-4,5-dihydro-1H-imidazole;

[1598][3-(2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-phenyl}-4,5-dihydro-imidazol-1-yl)-propyl]-diethyl-amine;

[1599]4-[3-(2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-phenyl}-4,5-dihydro-imidazol-1-yl)-propyl]-morpholine;

[1600]2-{2-[2-(2,5-Dichloro-phenyl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[1601]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-phenyl}-1,5-dimethyl-4,5-dihydro-1H-imidazole;

[1602]2-{2-[2-(2-Bromo-5-chloro-phenyl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[1603]2-{2-[2-(2,5-Dibromo-phenyl)-ethyl]-3-fluoro-phenyl}-4,5-dihydro-1H-imidazole;

[1604]2-{2-[2-(2-Bromo-5-chloro-phenyl)-ethyl]-3-fluoro-phenyl}-4,5-dihydro-1H-imidazole;

[1605]2-{2-[2-(5-Bromo-2-chloro-phenyl)-ethyl]-3-fluoro-phenyl}-4,5-dihydro-1H-imidazole;

[1606] 2-{2-[2-(3-Bromo-phenyl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[1607]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-phenyl}-1-(2,2,2-trifluoro-ethyl)-4,5-dihydro-1H-imidazole;

[1608]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-phenyl}-1,4,5-trimethyl-4,5-dihydro-1H-imidazole;

[1609]5-Benzyloxymethyl-2-{2-[2-(5-bromo-2-methoxy-phenyl)-ethyl]-phenyl}-1-methyl-4,5-dihydro-1H-imidazole;

[1610]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-phenyl}-4-ethyl-1-methyl-4,5-dihydro-1H-imidazole;

[1611]2-{2-[2-(5-Bromo-2-methyl-benzofuran-7-yl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[1612]2-{2-[2-(6-Bromo-benzo[1,3]dioxol-4-yl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-1H-imidazole;

[1613]2-{2-[2-(6-Bromo-benzo[1,3]dioxol-4-yl)-ethyl]-3-fluoro-phenyl}-4,5-dihydro-1H-imidazole;

[1614]2-{2-[2-(5-Bromo-benzo[b]thiophen-7-yl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[1615]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-chloro-phenyl}-4,5-dihydro-1H-imidazole;

[1616]2-{2-[2-(5-Bromo-2,3-dimethyl-benzofuran-7-yl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[1617](2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-phenyl}-3-methyl-4,5-dihydro-3H-imidazol-4-yl)-methanol;

[1618]2-{2-[2-(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-ethyl]-3-fluoro-phenyl}-4,5-dihydro-1H-imidazole;

[1619]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-phenyl}-5,5-dimethyl-4,5-dihydro-1H-imidazole;

[1620]2-{2-[2-(2,3,5-Trichloro-phenyl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[1621]2-{2-[2-(3-Bromo-naphthalen-1-yl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[1622]2-{2-[2-(3-Bromo-naphthalen-1-yl)-ethyl]-3-fluoro-phenyl}-4,5-dihydro-1H-imidazole;

[1623]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-phenyl}-5-methyl-4,5-dihydro-1H-imidazole;

[1624]4-Chloro-3-{2-[2-(4,5-dihydro-1H-imidazol-2-yl)-6-fluoro-phenyl]-ethyl}-benzontrile;

[1625]2-{2-[2-(5-Bromo-2-trifluoromethoxy-phenyl)-ethyl]-3-fluoro-phenyl}-4,5-dihydro-1H-imidazole;

[1626]2-{2-[2-(5-Bromo-2-trifluoromethoxy-phenyl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[1627]2-{2-[2-(5-Bromo-2-trifluoromethoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-1H-imidazole;

[1628]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-6-methoxy-phenyl}-4,5-dihydro-1H-imidazole;

[1629]2-{2-[2-(5-Bromo-benzofuran-7-yl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-1H-imidazole;

[1630]2-{2-[2-(5-Bromo-2-difluoromethoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-1H-imidazole;

[1631]3-{2-[2-Chloro-6-(4,5-dihydro-1H-imidazol-2-yl)-phenyl]-ethyl}-4-methoxy-benzonitrile;

[1632]2-{2-[2-(5-Bromo-benzofuran-7-yl)-ethyl]-3-ethoxy-phenyl}-4,5-dihydro-1H-imidazole;

[1633]7-{2-[2-Chloro-6-(4,5-dihydro-1H-imidazol-2-yl)-phenyl]-ethyl}-benzofuran-5-carbonitrile;

[1634]2-{2-[2-(8-Bromo-naphthalen-1-yl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-1H-imidazole;

[1635]2-{3-Chloro-2-[2-(2-methyl-biphenyl-3-yl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[1636]2-[2-(2-Biphenyl-3-yl-ethyl)-3-chloro-phenyl]-4,5-dihydro-1H-imidazole;

[1637][4-(2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-imidazol-1-yl)-pentyl]-diethyl-amine;

[1638]2-{2-[2-(4-Bromo-4′-methoxy-biphenyl-2-yl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-1H-imidazole;

[1639]2-{2-[2-(4-Bromo-2′-methoxy-biphenyl-2-yl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-1H-imidazole;

[1640]2-{2-[2-(4-Bromo-3′-methoxy-biphenyl-2-yl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-1H-imidazole;

[1641]2-{2-[2-(6-Bromo-2-methoxy-naphthalen-1-yl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-1H-imidazole;

[1642]2-[2-(2-Biphenyl-2-yl-ethyl)-3-chloro-phenyl]-4,5-dihydro-1H-imidazole;

[1643]2-{3-Chloro-2-[2-(4-fluoro-naphthalen-1-yl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[1644]2-{2-[2-(4-Bromo-2′-chloro-biphenyl-2-yl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-1H-imidazole;

[1645]2-{2-[2-(4-Bromo-3′-chloro-biphenyl-2-yl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-1H-imidazole;

[1646]7-{2-[2-(4,5-Dihydro-1H-imidazol-2-yl)-6-fluoro-phenyl]-ethyl}-benzofuran-5-carbonitrile;

[1647]2-{2-[2-(4-Bromo-4′-chloro-biphenyl-2-yl)-ethyl]-3-chloro-phenyl}-4,5dihydro-1H-imidazole;

[1648]2-{2-[2-(2,5-Dibromo-benzofuran-7-yl)-ethyl]-3-fluoro-phenyl}-4,5-dihydro-1H-imidazole;

[1649]2-{3-Fluoro-2-[2-(2-methoxy-5-trifluoromethyl-phenyl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[1650]2-{3-Fluoro-2-[2-(5-phenyl-benzofuran-7-yl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[1651]2-{2-[2-(5-Ethynyl-benzofuran-7-yl)-ethyl]-3-fluoro-phenyl}-4,5-dihydro-1H-imidazole;

[1652]2-{3-Fluoro-2-[2-(5-methanesulfonyl-benzofuran-7-yl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[1653]2-{3-Fluoro-2-[2-(5-pyrrol-1-yl-benzofuran-7-yl)-ethyl]-phenyl}-4,5-dihydro-1H-imidazole;

[1654]7-{2-[2-Fluoro-6-(1-isopropyl-4,5-dihydro-1H-imidazol-2-yl)-phenyl]-ethyl}-benzofuran-5-carbonitrile;

[1655]7-(2-{2-Fluoro-6-[1-(3-pyrrolidin-1-yl-propyl)-4,5-dihydro-1H-imidazol-2-yl]-phenyl}-ethyl)-benzofuran-5-carbonitrile;

[1656]7-{2-[2-Fluoro-6-(1-piperidin-4-ylmethyl-4,5-dihydro-1H-imidazol-2-yl)-phenyl]-ethyl}-benzofuran-5-carbonitrile;

[1657]4-(2-{2-[2-(5-Bromo-benzofuran-7-yl)-ethyl]-3-fluoro-phenyl}-4,5-dihydro-imidazol-1-ylmethyl)-piperidine;

[1658]2-{2-[2-(3-Bromo-naphthalen-1-yl)-ethyl]-3-fluoro-phenyl}-1-(3-pyrrolidin-1-yl-propyl)-4,5-dihydro-1H-imidazole;

[1659]2-{2-[2-(5-Bromo-benzofuran-7-yl)-ethyl]-3-fluoro-phenyl}-3a,4,5,6,7,7a-hexahydro-1H-benzoimidazole;

[1660]7-{2-[2-Fluoro-6-(3a,4,5,6,7,7a-hexahydro-1H-benzoimidazol-2-yl)-phenyl]-ethyl}-benzofuran-5-carbonitrile;

[1661]7-{2-[2-Chloro-6-(3a,4,5,6,7,7a-hexahydro-1H-benzoimidazol-2-yl)-phenyl]-ethyl}-benzofuran-5-carbonitrile;

[1662]2-{2-[2-(3-Bromo-naphthalen-1-yl)-ethyl]-3-chloro-phenyl}-3a,4,5,6,7,7a-hexahydro-1H-benzoimidazole;

[1663]2-{2-[2-(3-Bromo-naphthalen-1-yl)-ethyl]-3-fluoro-phenyl}-3a,4,5,6,7,7a-hexahydro-1H-benzoimidazole;

[1664]2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-phenyl}-3a,4,5,6,7,7a-hexahydro-1H-benzoimidazole;

[1665]2-{2-[2-(5-Bromo-2,3-dimethyl-benzofuran-7-yl)-ethyl]-3-fluoro-phenyl}-1-(3-pyrrolidin-1-yl-propyl)-4,5-dihydro-1H-imidazole;

[1666]2-{2-[2-(5-Bromo-benzofuran-7-yl)-ethyl]-3-fluoro-phenyl}-1H-imidazole;

[1667]2-{2-[2-(5-Bromo-benzofuran-7-yl)-ethyl]-3-fluoro-phenyl}-1-isopropyl-1H-imidazole;

[1668]2-{2-[2-(5-Bromo-benzofuran-7-yl)-ethyl]-3-fluoro-phenyl}-1-(3-pyrrolidin-1-yl-propyl)-1H-imidazole;

[1669]2-{2-[2-(5-Bromo-3-phenyl-benzofuran-7-yl)-ethyl]-3-fluoro-phenyl}-4,5-dihydro-1H-imidazole;

[1670]2-{2-[2-(5-Bromo-3-isopropyl-benzofuran-7-yl)-ethyl]-3-fluoro-phenyl}-4,5-dihydro-1H-imidazole;

[1671]2-{2-[2-(5-Bromo-2,3-dimethyl-benzofuran-7-yl)-ethyl]-3-fluoro-phenyl}-4,5-dihydro-1H-imidazole;

[1672]2-{2-[2-(3-Bromo-naphthalen-1-yl)-ethyl]-3-fluoro-phenyl}-1-isopropyl-4,5-dihydro-1H-imidazole;

[1673]2-{2-[2-(5-Bromo-benzo[b]thiophen-7-yl)-ethyl]-3-fluoro-phenyl}-3a,4,5,6,7,7a-hexahydro-1H-benzoimidazole;

[1674]3-{2-[2-Fluoro-6-(3a,4,5,6,7,7a-hexahydro-1H-benzoimidazol-2-yl)-phenyl]-ethyl}-4-methoxy-benzonitrile;

[1675]2-{2-[2-(5-Bromo-benzo[b]thiophen-7-yl)-ethyl]-3-fluoro-phenyl}-1-(3-pyrrolidin-1-yl-propyl)-4,5-dihydro-1H-imidazole;

[1676]7-(2-{2-Fluoro-6-[1-(3-pyrrolidin-1-yl-propyl)-4,5-dihydro-1H-imidazol-2-yl]-phenyl}-ethyl)-benzo[b]thiophene-5-carbonitrile;

[1677]2-{2-[2-(5-Bromo-benzo[b]thiophen-7-yl)-ethyl]-3-chloro-phenyl}-3a,4,5,6,7,7a-hexahydro-1H-benzoimidazole;

[1678]3-{2-[2-Chloro-6-(3a,4,5,6,7,7a-hexahydro-1H-benzoimidazol-2-yl)-phenyl]-ethyl}-4-methoxy-benzonitrile;

[1679]2-{2-[2-(5-Bromo-benzo[b]thiophen-7-yl)-ethyl]-3-chloro-phenyl}-1-(3-pyrrolidin-1-yl-propyl)-4,5-dihydro-1H-imidazole;

[1680]7-(2-{2-Chloro-6-[1-(3-pyrrolidin-1-yl-propyl)-4,5-dihydro-1H-imidazol-2-yl]-phenyl}-ethyl)-benzo[b]thiophene-5-carbonitrile;

[1681]7-{2-[2-Chloro-6-(4,5-dihydro-1H-imidazol-2-yl)-phenyl]-ethyl}-benzo[b]thiophene-5-carbonitrile;

[1682]7-{2-[2-(4,5-Dihydro-1H-imidazol-2-yl)-6-fluoro-phenyl]-ethyl}-benzo[b]thiophene-5-carbonitrile,and pharmaceutically acceptable salts thereof. Also included arecompositions containing the compounds listed in Table 4.

[1683] In a further embodiment, the pharmaceutical compositions of theinvention include compositions wherein the MC4-R binding compound is not5-(4-chloro-phenyl)-2,5-dihydro-3H-imidazo[2, 1-a]-isoindol-5-ol(MASPINDOL; Compound DT).

[1684] In another embodiment, the pharmaceutical compositions of theinvention include compositions wherein the MC4-R binding compound is not2-naphthalen-1-ylmethyl-4,5-dihydro-1H-imidazole (NAPHAZOLINE; CompoundAS);10-[2-(1-methyl-piperadin-2-yl)-ethyl]-2-methylsulfanyl-10H-phenothiazine(THORADIAZINE; THIODIAZINE; Compound AP);(2,6-dichloro-phenyl)-imidazolidin-2-ylidene-amine (CLONIDINE; CompoundAY); or 2-benzyl-4,5-dihydro-1H-imidazole (TOLAZOLINE; Compound AZ).

[1685] In another further embodiment, the pharmaceutical compositions ofthe invention includes compositions wherein the MC4-R binding compoundis not2-[2-(2,5-dichlorothiophen-3-ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydropyrimidine(Compound A);2[2-(2-chloro-6-fluoro-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydropyrimidine(Compound B);1-(6-bromo-2-chloro-quinolin-4-y1)-3-(2-diethylaminoethyl)-urea(Compound AN);2-[2-(2,6-difluorobenzylsulfanyl)-phenyl]-1,4,5,6-tetrahydropyrimidine(Compound AO); 1-(4-hydroxy-1,3,5-trimethyl-piperadin-4-yl)-ethanone(Compound AR); 4,6-dimethyl-2-piperazin-1-yl-pyrimidine (Compound FP);2-piperazin-1-yl-pyrimidine (Compound FR); 1-pyridin-2-yl-piperazine(Compound FS); 2-piperazin-1-yl-4-trifluoromethyl pyrimidine (CompoundFT);6-piperazin-1-yl-7-trifluoromethyl-thieno[3,2-b]pyridine-3-carboxylicacid methyl ester (Compound FU); 5-bromo-2-piperazin-1-yl)-pyrimidine(Compound FV); 1-(3-trifluoromethyl-pyridin-2-yl)-piperazine (CompoundFW); 1-(5-trifluoromethyl-pyridin-2-yl)-piperazine (Compound FX);piperazine (Compound KY); or (2-Hexyloxy-phenyl)-carbamic acid2-piperidin-1-yl-1-piperidin-1-ylmethyl-ethyl ester (Compound OQ).

[1686] The compounds of the present invention can be synthesized usingstandard methods of chemical synthesis and/or can be synthesized usingschemes described herein. Synthesis of specific compounds is discussedin detail in the Example sections below. Examples of syntheses ofseveral classes of compounds of the invention are outlined in theschemes below.

[1687] Scheme 1 depicts a method of synthesizing thiomethylene orhydroxymethylene compound of the invention.

[1688] 2-hydroxy or 2-mercapto benzoic acid is heated with the diaminein refluxing 1,2-dichlorobenzene to form the corresponding heterocycliccompound. The desired thioether or ether is formed by treating the thiolor alcohol with a corresponding halogenated compound.

[1689] Scheme 2 depicts a general preparation of ethanyl-linkedcompounds of the invention.

[1690] Scheme 2 shows a method of synthesizing ethanyl linked compoundsby treating α-tolunitrile with a lithium base in THF at −78° C. Ahalogenated alkylaryl compound is then added to form the ethanyllinkage. To form the heterocycle, hydrogen sulfide gas is bubbledthrough a solution of the nitrile and 1,3 diaminopropane. Afterformation, the product can then be obtained and purified using standardtechniques.

[1691] Scheme 3 depicts a method of preparing methylenethio linkedcompounds of the invention.

[1692] As depicted in Scheme 3, the methylenethio compounds of theinvention can be prepared by adding anhydrous K₂CO₃ to a thiophenolcompound (Ar—SH) in DMF. The solution is then stirred andbromomethyl-benzonitrile is subsequently added. The thioether is thenconverted to the heterocyclic compound by bubbling hydrogen sulfidethrough a solution of the thioether and 1,3 diaminopropane. Afterformation, the product can then be obtained and purified using standardtechniques.

[1693] As depicted in Scheme 4, cyclic amidines of the invention can beprepared by reacting 2-substituted benzonitrile with hydrogen sulfide toform a thiobenzamide. The resulting thiobenzamide is then treated withiodoethane to give a thiobenzimidic acid ethyl ester. In the presence ofhydrochloric acid, the thiobenzimidic acid ethyl ester is suspended intetrahydrofuran and treated with hydrogen sulfide. The resultingdithiobenzoic acid ethyl ester is then heated with various diamines, inthe presence or absence of an added catalyst such as silvertrifluoroacetate, to give cyclic amidines.

[1694] The invention is further illustrated by the following exampleswhich in no way should be construed as being further limiting. Thecontents of all references, pending patent applications and publishedpatent applications, cited throughout this application are herebyincorporated by reference. It should be understood that the animalmodels used throughout the examples are accepted animal models and thatthe demonstration of efficacy in these animal models is predictive ofefficacy in humans.

EXEMPLIFICATION OF THE INVENTION EXAMPLE 1 Synthesis of IntermediateCompounds

[1695] Synthesis of 2-(4,5-Dihydro-1H-imidazol-2-yl)-benzenethiol:

[1696] 21.6 mL (0.323 mol) of ethylenediamine was added to a suspensionof 20.0 g (0.112 mol) of thiosalicylic acid in 200 mL of1,2-dichlorobenzene, and refluxed under nitrogen for 4 h then cooled toca. 60° C. and 50 mL of methanol was added. The solution was allowed tostand at 22° C. overnight and the resulting yellow crystalline solid wascollected and washed with ether to give 10.6 g of pure product.

[1697] Synthesis of 2-(2-Naphthalen-1-yl-ethyl)-benzonitrile:

[1698] 5.6 mL (9.0 mmol) of n-butyllithium, 1.6 M in hexanes, was addedto a solution of 1.26 mL (911 mg, 9.00 mmol) of diisopropylamine in 50mL of THF (tetrahydrofuran) was cooled to −78° C. under nitrogen and viasyringe. The mixture was stirred at −78° C. for 1 hour and a solution of353 mg (3.00 mmol) of α-tolunitrile in 10 mL of THF was added. Thesolution was stirred at −78° C. for one additional hour and a solutionof 1.57 mL (9.00 mmol) of HMPA and 583 mg (3.30 mmol) of1-chloromethylnaphthalene in 10 mL of THF was added dropwise. Afterstirring for one additional hour at −78° C., the reaction was quenchedwith water and extracted with Et₂O (diethyl ether) (2×30 mL). Theorganic layer was washed with aqueous 1 N HCl (30 mL), water (3×30 mL),brine (30 mL) and dried (Na₂SO₄). The solvent was evaporated to give 735mg of crude product which is used directly next steps.

[1699] Synthesis of2-(5-Bromo-2-methoxy-phenylsulfanylmethyl)-benzonitrile:

[1700] As depicted in Scheme 6, 162 mg (1.18 mmol) of anhydrous K₂CO₃was added to a solution of 104 mg (0.470 mmol) of2-methoxy-5-bromo-thiophenol in 5 mL of DMF, stirred for 15 minutes at22° C. and 103 mg (0.520 mmol) of 2-bromomethyl-benzonitrile was added,then the reaction was capped and heated to 40° C. for 12 hours. Themixture was subsequently diluted with 5 mL of water, extracted withethyl acetate (2×10 mL), and the organic extracts washed with water(3×10 mL), brine (2×10 mL), and dried (Na₂SO₄). The solvent wasevaporated and the product was purified on silica gel (eluting with 9:1of hexane/ethyl acetate) to afford 102 mg of the product as a colorlessoil.

[1701] Synthesis of9,2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-thiobenzamide:

[1702] As shown in Scheme 7, hydrogen sulfide gas was bubbled into asolution of 2.75 g (7.8 mmol) of2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-benzonitrile in 20 mL ofethanol and triethylamine (5:4 v/v) for 10 minutes, and the solutionthen heated to 80° C. in a sealed pressure tube for 5 hours. Thereaction mixture was diluted with water and extracted with ethyl acetatetwice; organic extracts were washed with brine, dried (MgSO₄), filteredand evaporated to give 3.0 g of crude product which was used directly.

[1703] Synthesis of2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-thiobenzimidic acidethyl ester:

[1704] 6 mL (75 mmol) of iodoethane was added to a solution of 3.0 g(7.8 mmol) of2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-thiobenzamide in 50 mLof acetone (Scheme 8), heated to 80° C. for 2 hours and then stirred atroom temperature overnight. A white solid precipitated and was filteredto give 3.23 g of the iodide salt. The salt was neutralized bypartitioning between CH₂Cl₂ and 1 N aqueous sodium hydroxide. Afterdrying (MgSO₄) and evaporation of the organic layer, 2.8 g of crudepowder was obtained which was used directly.

[1705] Synthesis of2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-dithiobenzoic acid

[1706] As shown in Scheme 9, hydrogen sulfide gas (2 mL) was condensedinto a cooled (−78° C.) solution of 2.8 grams (6.8 mmol) of2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-thiobenzimidic acidethyl ester and 13.6 mL (13.6 mmol) of 1.0 M HCl/ether in 100 mL oftetrahydrofuran. The reaction was heated to 45° C. and stirred overnightin a sealed tube. The reaction mixture was diluted with water andextracted with methylene chloride once, organic layer was washed withbrine, dried (MgSO₄), filtered and evaporated to give a crude orangeoil. The oil was partially purified by chromatography through a shortcolumn of silica gel (eluting with 5:95 ethyl acetate/hexanes) whichresulted in 1.8 g of an orange powder which was used directly.

[1707] Synthesis of 5-bromo-7-bromomethyl-benzo [b]thiophene:

[1708] A suspension of NaH (washed with hexane) (9.4 g, 1.1 equiv) inDMF (1 L) at 0° C. was degassed with nitrogen. To this slurry was addeda solution of 4-bromo-2-methyl phenol (40 g, 1.0 equiv) in DMF (35 mL)was added dropwise, and the mixture was allowed to stir at 0° C. for 30min (hydrogen evolution ceased) before the addition of a solution of thecarbamoyl choloride (29 g, 1.1 equiv), then allowed to warm to roomtemperature overnight and the reaction was quenched by the addition ofwater. The solution was extracted with EtOAc, the organic phase washedwith water and brine, dried over Na₂SO₄, filtered and concentrated. Theresulting residue was triturated with hexane to givedimethyl-thiocarbamic acid O-(4-bromo-2-methylphenyl) ester (50.3 g,86%). The thiocarbamic acid O-ester (48.2 g) was heated in diphenylether(100 mL) at 230° C. for 10 hr, then cooled to room temperature, themixture was filtered through SiO₂ (hexane), concentrated, and filtered asecond time to give dimethyl-thiocarbamic acidS-(4-bromo-2-methylphenyl) ester (34.7 g, 72%).

[1709] To a solution of the thiocarbamic acid S-ester (34.7 g) in THF(500 mL) under an atmosphere of nitrogen was added a solution of KOH(17.8 g, 2.5 equiv) in MeOH (90 mL), the solution allowed to stir atroom temperature for 5 hr and quenched by the addition of 1N HCl,extracted with EtOAc and the organic phase was washed with brine, driedover Na₂SO₄, filtered and concentrated to give 4-bromo-2-methylbenzenethiol which was used immediately. The thiol was added dropwise toa solution of sodium ethoxide (10.3 g, 1.2 equiv) in EtOH (600 mL),allowed to stir for 30 min before the dropwise addition of2-bromo-1,1-diethoxyethane (23 mL, 1.2 equiv). The reaction mixture washeated at reflux for 4 hr, allowed to cool and stir at room temperatureovernight, then quenched by the addition of water and concentrated.Water and EtOAc were added, the phases separated, and the aqueous phasewas further extracted with EtOAc. The organic phase was dried overNa₂SO₄, filtered and concentrated. The crude product was purified bycolumn chromatography (SiO₂, 5% EtOAC in hexanes) to give4-bromo-1-(2,2-diethoxyethylsulfanyl)-2-methylbenzene (38.4 g, 88% for 2steps).

[1710] To the acetal (35.4 g) in toluene (550 mL) was added PPA (18 mL)at 100° C. The mixture was heated at 120° C. for 30 min, cooled to 90°C. and the toluene was decanted. Water was added and the mixture stirredvigorously at 90° C., and toluene was again decanted. This procedure wasrepeated two additional times and then the organic phase was dilutedwith EtOAc, washed with brine, dried over Na₂SO₄, filtered andconcentrated. The crude product was filtered through SiO₂ (hexane).Concentration gave 5-bromo-7-methyl-benzo[b]thiophene (10.4 g, 41%).

[1711] The thiophene (10.16 g, 1.0 equiv), NBS (8.76 g, 1.1 equiv), andbenzoyl peroxide (0.54 g, 0.05 equiv) were dissolved in CCl₄, heated toreflux under UV irradiation for 2 hr and then cooled to 0° C. andfiltered. The filtrate was evaporated. Repeated trituration with hexanegave 5-bromo-7-bromomethyl-benzo[b]thiophene (7.0 g). Concentration ofthe hexane gave an oil which was purified by column chromatography(SiO₂, hexane) to give additional product (total yield 9.96 g, 86%).

[1712] Synthesis of 4-bromo-2-bromomethyl-3′-chloro-biphenyl:

[1713] Barium hydroxide monohydrate (2.27 g, 2.0 equiv),4-bromo-1-iodo-2-methylbenzene (0.94 mL, 1.1 equiv), 3-chlorophenylboronic acid (0.94 g, 1.0 equiv), and palladiumtetrakis(triphenylphosphine) (0.14 g, 0.02 equiv) were combined andstirred in dioxane (15 mL) and water (5 mL), heated at reflux for 2 hrand then allowed to cool to room temperature. The solution wasconcentrated and the residue dissolved in CH₂Cl₂, washed with water andbrine and then dried over Na₂SO₄, filtered and concentrated. The residuewas purified by column chromatography (SiO₂, hexane) to give4-bromo-3′-chloro-2-methyl biphenyl (0.33 g, 21%).

[1714] The biphenyl (0.235 mg, 1.0 equiv) was dissolved in CCl₄ (5 mL),NBS added, and the solution was irradiated until starting material wasconsumed. The mixture was allowed to cool to room temperature and thenfiltered through celite. The filtrate was concentrated and the residuepurified by column chromatography (SiO₂, hexane) to give the desiredproduct (0.258 g, 60%).

[1715] Synthesis of 4-bromo-2-bromomethyl-1-trifluoromethoxybenzene:

[1716] LDA was prepared by the dropwise addition of n-BuLi (2.5 M inhexanes, 9.96 mL, 1.2 equiv) to a solution of DIPEA (3.49 mL, 1.2 equiv)in THF (40 mL) at 0° C. under an atmosphere of nitrogen. The solutionwas allowed to stir for 30 min at 0° C. and then cooled to −100° C. and1-bromo-4-trifluoromethoxybenzene (5.0 g, 1.0 equiv) was added dropwise.The reaction mixture was allowed to stir at −100° C. for 1.5 hr, carbondioxide gas was bubbled through the solution for 45 min, and allowed towarm to −60° C. during this time. The reaction was then allowed to warmto room temperature and stirred for 18 hrs. The solvents were evaporatedand the residue was dissolved in 1N NaOH (50 mL) and then washed withEt₂O (2×). The aqueous phase was acidified to pH=1 by the addition ofconc. HCl and then extracted with Et₂O. The organic phase was dried overNa₂SO₄, filtered, and concentrated. The residue was purified byfiltering through SiO₂ (94:5:1 CH₂Cl₂:MeOH:AcOH) to give the carboxylicacid (2.2 g, 37%).

[1717] To a solution of 5-bromo-2-trifluoromethoxy benzoic acid (2.2 g,1.0 equiv) in THF (80 mL) at 0° C. under an atmosphere of nitrogen wasadded dropwise a solution of borane-THF (1.0 M in THF, 19.3 mL, 2.5equiv). The solution was heated at 70° C. for 18 hr and then allowed tocool to room temperature and concentrated. The residue was dissolved inmethanol and the solvent evaporated (2×). The crude product was purifiedby column chromatography (SiO₂, 20% EtOAc in hexane) to give the desiredbenzylic alcohol (1.45 g, 69%).

[1718] To a suspension of PPh₃Br₂ (1.91 g, 1.2 equiv) in CCl₄ (40 mL) at0° C. was added dropwise a solution of(5-bromo-2-trifluoromethoxyphenyl)-methanol (1.02 g, 1.0 equiv) in CCl₄(5 mL). The reaction mixture was allowed to warm to room temperature,stirred for 2 hr, and then concentrated. Hexane was added to the residueand the suspension was filtered through SiO₂ (hexane) to give thedesired benzylic bromide (1.0 g, 80%).

[1719] Synthesis of 2-bromomethyl-1-methoxy4-trifluoromethyl-benzene:

[1720] A heterogeneous slurry of 5-iodosalicylic acid (5.28 g, 1.0equiv), dimethylsulfate (5.5 g, 2.2 equiv) and potassium carbonate (12.2g, 4.4 equiv) in acetone (40 mL) was allowed to reflux under anatmosphere of nitrogen overnight. After cooling to room temperature, thereaction contents were slowly poured into stirring water (250 mL). Themixture was acidified to pH<5 (conc. HCl) and allowed to stir for 30min. The precipitated solid was filtered, washed with water, andair-dried. The crude product was purified by column chromatography(SiO₂, 15% EtOAc in hexane) to yield the desired methyl ether (5.3 g,91%).

[1721] A mixture of methyl 5-iodo-2-methoxybenzoate (1.46 g, 1.0 equiv),sodium trifluoroacetate (2.72 g, 4.0 equiv) and copper(I) iodide (3.3 g,3.1 equiv) in toluene (15 mL) was allowed to reflux for 2 hr toazeotrope water. Upon removal of water, dry DMF (15 mL) was addeddropwise via addition funnel while the reaction temperature was raised.Toluene was removed by distillation until the internal reactiontemperature reached 140° C. The solution was held at this temperaturefor 1 hr and then the temperature was raised to 150° C. for 5 hr. Thereaction mixture was then allowed to cool to room temperature and stirovernight before being quenched by pouring into stirring water (100 mL).The solution was extracted with EtOAc (2×50 mL) and the organic phasewas washed with brine (25 mL), dried over Na₂SO₄, filtered andconcentrated. Purification of the residue by column chromatography(SiO₂, 15% EtOAc in hexane) gave the desired ester (0.4 g, 33%).

[1722] To a solution of DIBAL (1.0 M in CH₂Cl₂, 16 mL, 2.0 equiv) inCH₂Cl₂ (10 mL) at 0° C. was added a solution of methyl5-trifluoromethyl-2-methoxy benzoate (1.7 g, 1.0 equiv) in CH₂Cl₂ (7.5mL). The reaction mixture was allowed to stir for 3 hr at 0° C. and thenat room temperature overnight. After recooling to −15° C., the reactionwas quenched by the slow addition of 1N HCl (20 mL). The resultingmixture was allowed to stir at room temperature for 1 hr and then wasextracted with CH₂Cl₂. The organic phase was washed with brine, driedover Na₂SO₄, filtered and concentrated to give the desired alcohol (1.46g, 98%) which was used without further purification.

[1723] To a stirring solution of 5′-trifluoromethyl-2′-methoxybenzylalcohol (1.4 g, 1.0 equiv) in toluene (10 mL) at 0° C. under a anatmposhere of nitrogen was added PBr₃ (2.27 g, 1.2 equiv). The resultingsolution was allowed to stir at 0° C. for 30 min and then at roomtemperature overnight. After recooling to 0° C., water (10 mL) was addeddropwise. The solution was allowed to stir at 0° C. for 5 min, then atroom temperature for 3 hr. The mixture was extracted with EtOAc (2×25mL) and the organic phases were combined, washed with saturated aqueousNaHCO₃ (25 mL) and brine (25 mL), dried over Na₂SO₄, filtered andconcentrated to give the desired benzyl bromide (1.57 g, 87%).

[1724] Synthesis of 5-bromo-7-bromomethyl-2-methyl-benzofuran:

[1725] To a solution of 5-bromo-2-hydroxy-benzoic acid methyl ester (2.5g, 1.0 equiv) in DMF (20 mL) was added K₂CO₃ (4.5 g, 3.0 equiv) and thenpropargyl bromide (2.3 mL, 1.4 equiv). The resulting solution wasallowed to stir at room temperature for 16 hr and then diluted withwater and extracted with Et₂O. The organic phase was washed with 5% NaOHand brine and then dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by column chromatography (SiO₂, hexane/acetone) togive the desired phenyl ether (2.1 g, 70%).

[1726] The phenyl ether (2.1 g, 1.0 equiv) was dissolved indiethylaniline (20 mL) and to this solution was added CsF (1.7 g, 1.5equiv). After heating at 210° C. for 16 hr, the solution was allowed tocool to room temperature and diluted with Et₂O. The mixture was filteredthrough celite and the organic phase was washed with saturated aqueousNaHCO₃ and water, dried over Na₂SO₄, filtered and concentrated.Purification of the residue by column chromatography (SiO₂,hexane/acetone) to gave the desired benzofuran (1.1 g, 50%).

[1727] DIBAL (1.0 M in CH₂Cl₂, 4.1 mL, 2.5 equiv) was added to a stirredsolution of the methyl ester (0.4 g, 1.0 equiv) in CH₂Cl₂ (7 mL) at −10°C. The reaction mixture was allowed to warm to room temperature whilevigorously stirring and then quenched by the addition of saturatedaqueous potassium sodium tartrate. The solution was extracted withCH₂Cl₂, dried over Na₂SO₄, filtered and concentrated. Purification ofthe residue by column chromatography (SiO₂, hexane/acetone) gave thedesired alcohol (0.3 g, 76%).

[1728] To a solution of the alcohol (0.8 g, 1.0 equiv) in toluene (14mL) at 0° C. was added PBr₃ (0.4 mL, 1.1 equiv). The resulting solutionwas allowed to warm to room temperature. After recooling to 0° C., thereaction was quenched by the slow addition of water. The solution wasextracted with CH₂Cl₂ and the organic phase was dried over Na₂SO₄filtered, and concentrated. Purification of the residue by columnchromatography (SiO₂, hexane/acetone) gave the desired bromide (0.6 g,56%).

[1729] Synthesis of 5-bromo-7-bromomethyl-2,3-dimethyl-benzofuran:

[1730] To a solution of 5-bromo-2-hydroxy-benzoic acid methyl ester (5.0g, 1.0 equiv) in DMF (40 mL) at room temperature was added3-bromo-butan-2-one (4.0 g, 1.4 equiv), K₂CO₃ (9.0 g, 3 equiv), and KI(11.0 g, 3.0 equiv). The reaction mixture was allowed to stir at roomtemperature for 16 hr and then quenched by the addition of water. Thesolution was extracted with EtOAc and the organic phase was dried overNa₂SO₄, filtered and concentrated. Purification of the residue by columnchromatography (SiO₂, hexane/acetone) gave the desired ether (5.5 g,85%).

[1731] The ether (1.0 g) was dissolved in H₂SO₄ (1.5 mL) and stirred atroom temperature for 16 hr. The reaction mixture was diluted with MeOHand water and then extracted with EtOAc. The organic phase was driedover Na₂SO₄, filtered and concentrated. The residue was purified bycolumn chromatography (SiO₂, hexane/acetone) to give the desiredbenzofuran (0.2 g, 20%).

[1732] A solution of the methyl ester (1.0 g, 1.0 equiv) in CH₂Cl₂ (7mL) was cooled to −10° C. and treated with DIBAL (1.0 M in CH₂Cl₂, 12mL, 3.25 equiv). The reaction mixture was allowed to warm to roomtemperature, quenched by the addition of saturated aqueous potassiumsodium tartrate, and extracted with CH₂Cl₂. The organic phase was driedover Na₂SO₄, filtered, and concentrated. Purification of the residue bycolumn chromatography (SiO₂, hexane/acetone) gave the desired alcohol(0.9 g, 97%).

[1733] To a solution of the alcohol (0.9 g, 1.0 equiv) in toluene (14mL) at 0° C. was added PBr₃ (0.4 mL, 1.1 equiv). The resulting solutionwas allowed to warm to room temperature. After recooling to 0° C., thereaction was quenched by the slow addition of water. The solution wasextracted with CH₂Cl₂, and the organic phase was dried over Na₂SO₄filtered, and concentrated. Purification of the residue by columnchromatography (SiO₂, hexane/acetone) gave the desired bromide (1.1 g,100%).

[1734] Synthesis of 6-bromo-4-bromomethyl-benzo[1,3]dioxole:

[1735] To a mixture of potassium fluoride (0.24 g, 9.0 equiv) and5-bromo-2,3-dihydroxy-benzaldehyde (0.10 g, 1.0 equiv) in DMF (5 ml)under an inert atmosphere was added dibromomethane (0.03 mL, 1.0 equiv).The reaction mixture was heated at 140° C. for 3 hr and then allowed tocool to room temperature and quenched by the addition of water. Thesolution was extracted with diethyl ether and the organic phase waswashed with 1N NaOH and brine, and dried over Na₂SO₄, filtered, andconcentrated to give the desired aldehyde (0.06 g, 57%) which was usedwithout further purification.

[1736] Sodium borohydride (0.018 g, 1.1 equiv) was slowly added to asolution of the aldehyde (0.10 g, 1.0 equiv) in MeOH (5 mL) at 0° C.After 20 min, the reaction was quenched by the addition of 1N NaOH andconcentrated. The residue was diluted with water and extracted withEtOAc. The organic phase was washed with brine, dried over Na₂SO₄,filtered, and concentrated to give the desired alcohol (0.08 g, 81%)which was used without further purification.

[1737] A solution of the alcohol (0.62 g, 1.0 equiv) in Et₂O (5 mL) wascooled to 0° C. under an inert atmosphere. To this cooled solution wasadded PBr₃ (0.25 mL, 1.0 equiv) dropwise. After 20 min, the reactioncontents were poured onto ice and diluted with 1N NaOH. The solution wasextracted with EtOAc and the organic phase was washed with brine, driedover Na₂SO₄, filtered, and concentrated to give the desired alcohol.Purification of the residue by filtration through SiO₂ (EtOAc) gave thedesired bromide (0.42 g, 53%).

[1738] Synthesis oftert-butyl-(1-chloromethyl-naphthalen-2-yloxy)-dimethyl-silane:

[1739] To a solution of 2-hydroxy-naphthalene-1-carbaldehyde (3.0 g, 1.0equiv) in DMF under an inert atmosphere was added imidazole (1.31 g, 1.1equiv) and tert-butyl-chloro-dimethyl-silane (2.88 g, 1.1 equiv). Thereaction mixture was allowed to stir at room temperature for 20 min andwas then quenched by the addition of water. The solution was extractedwith EtOAc, washed with brine, dried over Na₂SO₄, filtered, andconcentrated to give the protected alcohol which was used withoutfurther purification.

[1740] To a solution of the aldehyde (3.3 g, 2.0 equiv) in THF at 0° C.under an inert atmosphere was added LiAlH4 (0.22 g, 1.0 equiv). Thereaction mixture was allowed to stir for 45 min and then quenched by theaddition of water and allowed to stir overnight at room temperature. Thecrude mixture was filtered through SiO₂ (EtOAc) and the filtrate waswashed with brine, dried over Na₂SO₄, filtered, and concentrated. Theresidue was used directly without purification.

[1741] Thionyl chloride (0.34 g, 1.5 equiv) was added dropwise to asolution of the alcohol (0.50 g, 1.0 equiv) in CH₂Cl₂. The solution wasallowed to stir for 20 min at room temperature and then concentrated.Purification of the residue by column chromatography (SiO₂, hexane) gavethe desired chloride (0.40 g, 68%).

[1742] Synthesis of 2-(2-naphthalene-1-yl-ethyl)-benzonitrile:

[1743] A solution of the nitrile (2 mL, 1.0 equiv) and HMPA (3.3 mL, 1.1equiv) in THF (50 mL) was cooled to −78° C. under an atmosphere ofargon. To this solution was added LDA (2 M in THF, 9.4 mL, 1.1 equiv).The dark red solution was allowed to stir for 15 min and then1-chloromethylnaphthalene (3.3 g, 1.1 equiv) was added. The reaction wasquenched after 1.5 hr by the addition of saturated aqueous NH₄Cl. Themixture was diluted with EtOAc and water, the organic and aqueous phasesseparated, and the organic phase further washed with brine, dried overNa₂SO₄, filtered, and concentrated. The residue was purified by columnchromatography (SiO₂, 10% EtOAc in hexane) to give the desired product(2.06 g, 47%).

[1744] A similar procedure can be used to couple a variety ofbromomethyl- or chloromethyl-aryls to substituted or unsubstitutedtolunitriles.

[1745] Synthesis of2-[2-(5-bromo-2-difluoromethoxyphenyl)-ethyl]-3-chlorobenzonitrile:

[1746] A solution of2-[2-(5-bromo-2-methoxyphenyl)-ethyl]-3-chlorobenzonitrile (0.187 g, 1.0equiv) in CH₂Cl₂ (2.5 mL) was allowed to stir under an atmosphere ofargon at −78° C. To this solution was added boron tribromide (1.0 M inCH₂Cl₂, 2.65 mL, 5.0 equiv). After 15 min at −78° C., the solution wasallowed to warm to room temperature and stir overnight. The reaction wasquenched by the addition of water and the solution was extracted withEtOAc. The organic phase was dried over Na₂SO₄, filtered andconcentrated. The residue was purified by column chromotagraphy (SiO₂,20% EtOAc in hexane) to give2-[2-(5-bromo-2-hydroxyphenyl)-ethyl]-3-chlorobenzonitrile (0.144 g,81%).

[1747] To a solution of the phenol (0.144 g, 1.0 equiv) in isopropanol(8 mL) at room temperature was added KOH (85%, 0.284 g, 10.0 equiv).Chlorodifluoromethane was bubbled through the heterogeneous mixture forapproximately 3 minutes at room temperature and then for 3 minutes whileheating at 65° C. After 1 hour at 65° C., the reaction mixture wasallowed to cool to room temperature and diluted with EtOAc. The solutionwas washed with 1N HCl and then dried over Na₂SO₄, filtered andconcentrated to give the desired product in quantitative yield.

[1748] Synthesis of 3-(2-naphthalen-1 yl-ethyl)-pyridine-2-carbonitrile:

[1749] To a solution of the amide (4.02 g, 1.0 equiv) in TBF (80 mL)under an atmosphere of argon at −40° C. was added n-BuLi (2.5 M inhexane, 17.2 mL, 2.05 equiv) and then NaBr (0.22 g, 0.1 equiv). Thesolution was allowed to stir for 30 min before the addition of asolution of 1-chloromethylnaphthalene (4.06 g, 1.1 equiv) in THF (15mL). The reaction was quenched after 1.5 hr by the addition of water andthen allowed to warm to room tempearature and extracted with EtOAc. Theorganic phase was dried over Na₂SO₄, filtered and concentrated to givethe desired product in quantitative yield which was used directly in thenext step.

[1750] The amide (3.6 g, 1.0 equiv) was dissolved in POCl₃ (10 mL, 10.0equiv). The solution was heated at reflux for 2 hours and then wasallowed to cool to room temperature and basified with 6N NaOH to pH=8.The basic solution was allowed to stir at room temperature for 1.5 hoursand then diluted with Et₂O. After separation of aqueous and organicphases, the organic phase was further extracted with Et₂O. The organicphase was washed with water and brine, dried over Na₂SO₄, filtered andconcentrated. The residue was purified by column chromatography (SiO₂,40% EtOAc in hexane) to give the desired product (1.6 g, 57%).

[1751] Synthesis of 2-[2-(5-bromo-2-methoxyphenyl)-ethyl]-3-fluorobenzoic acid:

[1752] A solution of 3-fluoro-2-methylbenzoic acid (5.0 g, 1.0 equiv) inTHF (175 mL) was cooled to −78° C. under an atmosphere of argon. TMEDA(9.86 mL, 2.0 equiv) was added via syringe. s-BuLi (1.4 M incyclohexane, 49 mL, 2.1 equiv) was added dropwise via addition funnelover 30 min. After stirring for 2.5 hr, the bromide (13.7 g, 1.5 equiv)in THF (25 mL) was added dropwise. Upon completion of the addition, thesolution was allowed to stir and warm to room temperature overnight. Thereaction was quenched by the addition of water and then diluted withhexanes. The aqueous and organic phases were separated and the organicphase was washed with water. The aqueous phase was acidified to pH=1with 1N HCl and then extracted with EtOAc. The resulting organicsolution was dried over Na₂SO₄, filtered and concentrated. The residuewas rinsed with dichloromethane, filtered, and dried to give the desiredproduct (7.6 g, 66%).

[1753] A similar procedure can be used to couple a variety ofbromomethyl- or chloromethyl-aryls to substituted or unsubstituted arylcarboxylic acids.

[1754] Synthesis of2-[2-(5-cyano-benzofuran-7-yl)-ethyl]-3-fluoro-benzoic acid:

[1755] To a solution of2-[2-(5-bromo-benzofuran-7-yl)-ethyl]-3-fluoro-benzoic acid (1.5 g) inMeOH (5 mL) was added of conc. H₂SO₄ (0.2 mL). The resulting reactionmixture was heated at reflux for 16 hr and then cooled to roomtemperature, quenched with saturated aqueous NaHCO₃ (10 mL) andextracted with EtOAc (3×25 mL). The organic phase was dried over MgSO₄,filtered, and concentrated. The residue was purified by columnchromatography (SiO₂, EtOAc/hexane) to give the desired methyl ester(1.5 g, 95%).

[1756] To a solution of2-[2-(5-bromo-benzofuran-7-yl)-ethyl]-3-fluoro-benzoic acid methyl ester(1.5 g, 1.0 equiv) in DMF (16 mL) was added CuCN (0.7 g, 2.0 equiv). Theresulting reaction mixture was allowed to heat for 16 hr beforeadditional CuCN (0.7 g, 2.0 equiv) was added. After heating for 6 hr,the reaction mixture was allowed to cool to room temperature, dilutedwith EtOAc and filtered through celite. The filtrate was washed withsaturated aqueous NaHCO₃ and water and then dried over MgSO₄, filtered,and concentrated. Purification of the residue by column chromatography(SiO₂, EtOAc/hexane) gave the desired nitrile (0.6 g, 50%).

[1757] To a solution of the methyl ester (0.5 g, 1.0 equiv) in THF (4mL) and H₂O (2 mL) was added LiOH (0.1 g, 2.0 equiv). The mixture wasallowed to stir at room temperature for 16 hr and then the reactionmixture was diluted with H₂O and washed with hexane. The aqueous phasewas acidified with 1N HCl and extracted with EtOAc. The resultingorganic phase was dried over Na₂SO₄, filtered, and concentrated to givethe desired acid (0.4 g, 93%) which was used without furtherpurification.

EXAMPLE 2 Synthesis of Compounds B, HO, and IZ

[1758] Synthesis of Compound B

[1759]2-[2-(2-Chloro-6-fluoro-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine;hydrochloride (Compound B). To a solution of 750 mg (3.90 mmol) of2-(1,4,5,6-Tetrahydro-pyrimidin-2-yl)-benzenethiol was added 1.04 g(5.81 mmol) of 1-Chloro-2-chloromethyl-3-fluoro-benzene. The solutionwas stirred overnight at 22° C. and 2-3 mL of ether was added to inducecrystallization. The crystals were collected and washed with ether togive 1.34 g of product.

[1760] NMR Data for Compound B

[1761]¹H NMR (300 MHz, CD₃OD) δ2.01-2.09 (2H, m), 3.49 (4H, br t, J=5.8Hz), 4.28 (2H, s), 7.01-7.07 (1H, m), 7.22-7.33 (2H, m), 7.48 (2H, m),7.56-7.64 (1H, m), 7.75 (1H, d, J=7.8 Hz)

[1762] Synthesis of Compound HO:

[1763]2-[2-(2-Naphthalen-1-yl-ethyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine(Compound HO). Hydrogen sulfide gas was bubbled through a solution of735 mg of crude 2-(2-Naphthalen-1-yl-ethyl)-benzonitrile in 5 mL of1,3-diaminopropane for 5 minutes, as depicted in Scheme 23. The reactionwas capped and heated to 80° C. for 72 hours. The reaction mixture wasthen diluted with 5 mL of water and extracted with ethyl acetate (2×10mL). The organic extracts were washed with water (3×10 mL), brine (2×10mL), dried (Na₂SO₄) and the solvent was evaporated. The residue waspurified on silica gel (eluting with 90:10:1:1 ofdichloromethane/methanol/water/formic acid) to afford 310 mg of theformate salt of the product as a colorless oil.

[1764] NM1R Data for Compound HO:

[1765]¹H NMR (300 MHz, CDCl₃) δ1.35-1.50 (2H, m), 2.80-2.95 (4H, m),3.03 (2H, t, J=6.8), 3.30 (2H, t, J=6.8), 6.77 (1H, d, J=6.9), 7.03-7.30(3H, m), 7.30-7.57 (4H, m), 7.67 (1H, d, J=8.1), 7.80-7.90 (1H, m),7.94-8.03 (1H, m), 8.06 (2H, brs, formate salt).

[1766] Synthesis of Compound IZ:

[1767]2-[2-(5-Bromo-2-methoxy-phenylsulfanylmethyl)-phenyl]-1,4,5-6-tetrahydro-pyrimidine.(Compound IZ) Compound DV was obtained from2-(5-Bromo-2-methoxy-phenylsulfanylmethyl)-benzonitrile,1,3-propanediamine and hydrogen sulfide in 73% yield by a procedureanalogous to that used for the preparation of2-[2-(2-Naphthalen-1-yl-ethyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidinedescribed above. Following chromatography, the material was converted tothe hydrochloride salt and recrystallized from methanol/ether.

[1768] NMR Data for Compound IZ

[1769]¹H NMR (300 MHz, DMSO-d₆) δ1.95-2.10 (2H, m), 3.45-3.55 (4H, m),3.86 (3H, s), 4.40 (2H, s), 6.97-7.04 (1H, m), 7.36-7.65 (6H, m), 10.03(2H, s, hydrochloride salt).

[1770] Synthesis of Compound UZ:

[1771]2-{2[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl}-3a,4,5,6,7,7a-hexahydro-1H-benzoimidazole(Compound UZ). As shown in Scheme 25, a solution of 187 mg (0.43 mmol)of 2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-dithiobenzoic acidethyl ester in 2.5 mL of trans-1,2 diaminocyclohexane was heated to 110°C. in a sealed pressure tube for 12 hours. The reaction mixture wasdiluted with water and extracted with methylene chloride twice. Theorganic extracts were washed with brine, dried (MgSO₄) and evaporated.The residue was chromatographed on silica gel (eluting with 95:5CH₂Cl₂/methanol) to give a yellow oil. The oil was treated withmethanolic HCl and evaporated to yield 34 mg of product as a purehydrochloride salt.

[1772] NMR Data for Compound UZ

[1773]¹H NMR (300 MHz, CD₃OD) δ1.41-1.58 (2 H, br m), 1.64-1.80 (2 H, brm), 1.98 (2 H, br m), 2.30 (2 H, br m), 2.78-2.97 (2 H, m), 3.08 (1 H,m), 3.22-3.36 (1 H, m), 3.61 (2 H, m), 3.59(3 H, s), 6.81 (H, d,J=8.7Hz), 7.21 (H, m), 7.34(1 H, dd, J=2.5, 8.6 Hz), 7.42 (2 H, m), 7.75(1 H, dd, J=2.3, 7.0 Hz).

EXAMPLE 3 Synthesis of Compounds TB, AAP, ZF, ZO, ABB, ABC, and ZM

[1774] Synthesis of2-{2-[2-(5-bromo-2-methoxyphenyl)-ethyl]-3-chlorophenyl}-4,5-dihydro-1H-imidazole(Compound TB):

[1775] 2-[2-(5-bromo-2-hydroxyphenyl)-ethyl]-3-chlorobenzonitrile (2.08g, 1.0 equiv) was stirred in ethylene diamine (3 mL, 4.0 equiv) at roomtemperature. Hydrogen sulfide was bubbled through the solution forapproximately 5 minutes. The mixture was heated in a sealed tube at 100°C. for 18 hr. After cooling to room temperature, the residue wasdissolved in water and the solution extracted with EtOAc. The organicphase was dried over Na₂SO₄, filtered and concentrated to give thedesired product (1.61 g, 69%).

[1776] Synthesis of2-{2-[2-(5-bromo-2-methoxyphenyl)-ethyl]-3-fluorophenyl}-1-isopropyl-4,5-dihydro-1H-imidazole(Compound AAP):

[1777] To a solution of the carboxylic acid (1.1 g, 1.0 equiv) and DIPEA(1.16 mL, 2.2 equiv) in DMF (15 mL) was addedfluoro-N,N,N′-tetramethylformamidinium hexafluorophosphate (TFFH, 0.88g, 1.1 equiv). The mixture was allowed to stir at room temperature for 1hr before the addition of ethanolamine (0.37 mL, 2.0 equiv). Thesolution was allowed to stir at room temperature overnight and thenquenched by the addition of water. The solution was extracted withEtOAc, dried over Na₂SO₄, filtered and concentrated. Purification of theresidue by column chromatography (SiO₂, 50-100% EtOAc in hexane) gavethe desired hydroxy amide (1.1 g, 100%).

[1778] A solution of the hydroxy amide (0.51 g, 1.0 equiv) in thionylchloride (2.2 mL, 20 equiv) was heated at reflux for 4 hr and thenallowed to cool to room temperature and concentrated. The residue wasdissolved in chloroform (2 mL) and stirred under an atmosphere ofnitrogen. To this solution was added triethylamine (0.43 mL, 2.0 equiv)and isopropylamine (0.26 mL, 2.0 equiv). The reaction mixture wasallowed to stir overnight at room temperature and then quenched by theaddition of 1N NaOH. EtOAc was added to the solution and the aqueous andorganic phases separated. The organic phase was washed with 1N NaOH andbrine, dried over MgSO₄, filtered and concentrated. The residue waspurified by column chromatography (SiO₂, 89:10:1 CH₂Cl₂:MeOH:NH₄OH) togive the desired product (0.27 g, 51%).

[1779] Synthesis of3-(2-{2-[2-(5-bromo-2-methoxyphenyl)-ethyl]-3-chlorophenyl}-4,5-dihydroimidazol-1-yl)-propionitrile(Compound ZF):

[1780] To a stirring slurry of the amidine (0.1 g, 1.0 equiv) and basicdowex (0.2 g, 8 wt %/mmol) in EtOH (0.85 mL) was added freshly distilledacrylonitrile (0.033 mL, 2.0 equiv). The mixture was heated at 60° C. ina sealed tube for 5.5 hr and then allowed to cool to room temperature.The slurry was filtered and the solid rinsed with EtOH. The filtrate wasconcentrated and the residue purified by column chromatography (SiO₂,90:10:1:1 CH₂Cl₂:MeOH:H₂O:HCOOH) to give the desired product (0.049 g,43%).

[1781] Synthesis of2-{2-[2-(5-bromo-2-methoxyphenyl)-ethyl]-3-chlorobenzyl}-(4,5-dihydro-1H-imidazol-2-yl)-amine(Compound ZP):

[1782] The benzonitrile (1.0 g, 1.0 equiv) was dissolved in THE (5 mL)and cooled to −78° C. under an atmosphere of argon. To this cooledsolution was added LiAlH₄ (1.0 M 20 in THF, 3.7 mL, 1.3 equiv) dropwise.The reaction mixture was allowed to stir while warming to roomtemperature over 30 minutes. The reaction contents were poured onto iceand the resulting solution was basified by the addition of 6N NaOH. Themixture was extracted with ether and then the organic phase was driedover Na₂SO₄, filtered, and concentrated. The residue was purified bycolumn chromatography (SiO₂, CH₂Cl₂/MeOH gradient) to give the desiredbenzyl amine (0.6 g, 60%).

[1783] To a solution of 2-methylsulfanyl-4,5-dihydro-1H-imidazolehydroiodide (1.22 g, 1.0 equiv) in CH₂Cl₂ (25 mL) under an atmosphere ofargon at 0° C. was added triethylamine (1.5 mL, 2.2 equiv) and then3-methoxybenzoyl chloride (0.78 mL, 1.1 equiv) dropwise. Thereactionmixture was allowed to warm to room temperature and stir for 24 hr.After concentration, the resulting residue was diluted with EtOAc (50mL) and hexane (50 mL). The mixture was filtered and then the filtrateconcentrated and dried under vacuum to give a quantitative yield of(3-methoxyphenyl)-(2-methylsulfanyl-4,5-dihydroimidazol-1-yl)-methanonewhich was used directly in the next step.

[1784] A solution of the benzyl amine (0.252 g, 1.0 equiv) and thethiomethylimidazole (0.178 g, 1.0 equiv) in MeOH (4 mL) and HOAc (1 mL)was heated at 60° C. for 2 days. The solution was allowed to cool toroom temperature and then concentrated. The residue was partitionedbetween CH₂Cl₂ and saturated aqueous NaHCO₃ and the organic phase wasseparated, dried over Na₂SO₄, filtered, and concentrated. The crudeproduct was purified by column chromatography (SiO₂, CH₂Cl₂:MeOH:NH₃40:10:2) to give the desired product.

[1785] Synthesis of3-{2-[2-(5-bromo-2-methoxyphenyl)-ethyl]-3-chlorophenyl}-(5,6-dihydroimidazo[2,1-b]thiazole(Compound ZQ):

[1786] To a solution of methylmagnesium bromide (3.0 M in diethyl ether,2.85 mL, 3.0 equiv) in THF (6 mL) under an atmosphere of argon at roomtemperature was added a solution of the nitrile (1.0 g, 1.0 equiv) inTHF (6 mL). The resulting solution was allowed to stir at 60° C. for 16hr and then allowed to cool to room temperature. The reaction mixturewas poured into a mixture of diethyl ether (100 mL) and 1N aqueous HCl(100 mL). The aqueous phase was separated, transferred to around-bottomed flask, and heated at reflux for 1 hr. After cooling toroom temperature, the solution was extracted with diethyl ether (3×50mL). The organic phase was washed with saturated aqueous NaHCO₃ (50 mL)and brine (50 mL), dried over MgSO₄, filtered, and concentrated. Theresidue was purified by column chromatography (SiO₂, 15% EtOAc inhexanes) to give the desired methyl ketone (0.85 g, 81%).

[1787] To a solution of the methyl ketone (0.78 g, 1.0 equiv) inacetonitrile (12 mL) under an atmosphere of argon at room temperaturewas added [hydroxyl(tosyloxy)iodo]benzene (0.83 g, 1 equiv). Thesolution was heated at reflux for 4 hr and then the solvent wasevaporated. The residue was dissolved in ethanol (20 mL) and to this wasadded 2-imidazolidinethione (0.22 g, 1 equiv). The solution was heatedat reflux for 4 hr and then allowed to cool to room temperature. Thesolvent was evaporated and the residue was diluted with EtOAc and thenwashed with saturated aqueous NaHCO₃ and brine. The aqueous phase wasdried over MgSO₄, filtered, and concentrated. The residue was purifiedby column chromatography (SiO₂, 30% EtOAc in hexanes) to give thedesired heterocycle (0.40 g, 42%).

[1788] Synthesis of2-{2-[2-(5-bromo-2-methoxyphenyl)-ethyl]-3-chlorophenyl}1-4,5-dihydro-imidazol-1-yl)-aceticacid (Compound ABB):

[1789] A solution of the t-butyl ester (0.046 g, 1.0 equiv) was stirredin a solution of HCl in dioxane (4N, 0.7 mL) at room temperatureovernight. Concentration of the solvent and purification by columnchromatography (SiO₂, 90:10:1:1 CH₂Cl₂:MeOH:H₂O:HCOOH) gave the desiredcarboxylic acid (0.016 g, 50%).

[1790] Synthesis of(2-{2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-phenyl}1-3-methyl-4,5-dihydro-3H-imidazol-4-yl)-methanol(Compound ABC):

[1791] To a solution of the imidazoline (0.11 g, 1.0 equiv) in CH₂Cl₂under an atmosphere of nitrogen was added iodotrimethylsilane (0.5 mL,15 equiv). After 42.5 hours, additional iodotrimethylsilane (0.5 mL, 15equiv) was added. After 67 hours total reaction time, the solution wasconcentrated under nitrogen and the residue was diluted with CH₂Cl₂. Thesolution was washed with saturated aqueous NaHCO₃ and brine before beingdried over MgSO₄, filtered and concentrated. The residue was purified byRP HPLC and the resulting product was converted to the hydrochloridesalt (6 mg, 6%).

[1792] Synthesis of[2-(1-[2-(4,5-dihydro-1H-imidazol-2-yl)-6-fluoro-phenyl]-ethyl]-naphthalen-2-yloxy)-ethyl]-dimethylamine(Compound ZM):

[1793] To a solution of the amidine (1.62 g, 1.0 equiv) in CH₂Cl₂ at 0°C. were added triethylamine (1.0 mL, 2.0 equiv) anddi-tert-butyl-dicarbonate (0.95 g, 1.2 equiv). The reaction mixture wasallowed to warm to room temperature and stir for 2 hr. The reaction wasquenched by the addition of water and the solution was extracted withEtOAc. The organic phase was washed with brine, dried over Na₂SO₄,filtered, and concentrated. Purification of the residue by columnchromatography (SiO₂, 99:1 CH₂Cl₂:1% NH₃ in MeOH) gave the desiredproduct (1.5 g, 76%).

[1794] TBAF (1.0 M in THF, 5.5 mL, 1.5 equiv) was added to a solution ofthe protected alcohol (2.0 g, 1.0 equiv) in THF. The solution wasallowed to stir for 30 min and was then quenched by the addition ofwater. The solution was extracted with EtOAc. The organic phase waswashed with 1N HCl and brine, dried over Na₂SO₄, filtered, andconcentrated. Purification of the residue by column chromatography(SiO₂, 99:1 CH₂Cl₂:1% NH₃ in MeOH) gave the desired product (0.90 g,58%).

[1795] A heterogeneous mixture of the naphthol (0.097 g, 1.0 equiv) andcesium carbonate 0.18 g, 2.5 equiv) was heated at 60° C. for 20 minbefore the addition of dimethylamino ethyl chloride (0.034 g, 1.1equiv). The reaction mixture was allowed to cool to room temperature andstir overnight. The reaction was quenched by the addition of water andthe solution was extracted with EtOAc. The organic phase was washed withbrine, s were combined, washed with brine, dried over Na₂SO₄, filtered,and concentrated. Purification of the residue by column chromatography(SiO₂, 99:1 CH₂Cl₂:1% NH₃ in MeOH) gave the protected amidine.Deprotection and salt formation with 4M HCl in dioxane at 60° C. gavethe desired product as its bishydrochloride salt (0.011 g, 11%). TABLE 1Physical Data of Selected MC4-R Binding Compounds Exact ES- Mass LRMSMelt (free found Point ID Name Molecular Formula Base) (M + H) (° C.) I2-[2-(4-Benzyloxy-benzylsulfanyl)-phenyl]- C₂₄H₂₄N₂OS 388.16 389.6178-179 1,4,5,6-tetrahydro-pyrimidine; hydrochloride HCl M2-[2-(2-Iodo-benzylsulfanyl)-phenyl]- C₁₇H₁₇IN₂S 408.02 409 207-2091,4,5,6-tetrahydro-pyrimidine; HCl hydrochloride N2-[2-(2-Methoxy-5-nitro-benzylsulfanyl)- C₁₈H₁₉N₃O₃S 357.11 358.1239-241 phenyl]-1,4,5,6-tetrahydro-pyrimidine; HBr hydrobromide O2-[2-(Naphthalen-1-ylmethylsulfanyl)- C₂₁H₂₀N₂S 332.13 333.1 207-208phenyl]-1,4,5,6-tetrahydro-pyrimidine; HCl hydrochloride Q2-[2-(3-Chloro-benzylsulfanyl)-phenyl]- C₁₇H₁₇ClN₂S 316.08 317  224-225.5 1,4,5,6-tetrahydro-pyrimidine; HBr hydrobromide AI2-[2-(2,5-Dimethoxy-benzylsulfanyl)- C₁₉H₂₂N₂O₂S 342.14 343.2 201-202phenyl]-1,4,5,6-tetrahydro-pyrimidine; HCl hydrochloride Z2-[2-(3-Bromo-benzylsulfanyl)-phenyl]- C₁₇H₁₇BrN₂S 360.03 361 210-2111,4,5,6-tetrahydro-pyrimidine; HBr hydrobromide B2-[2-(2-Chloro-6-fluoro-benzylsulfanyl)- C₁₇H₁₆ClFN₂S 334.07 335 232-233phenyl]-1,4,5,6-tetrahydro-pyrimidine; HCl hydrochloride AE2-[2-(2-Iodo-benzylsulfanyl)-phenyl]-4,5- C₁₆H₁₅IN₂S 394 394.9 184-185dihydro-1H-imidazole; hydrochloride HCl AF2-[2-(2-Methoxy-5-nitro-benzylsulfanyl)- C₁₇H₁₇N₃O₃ 343.1 344.1 253-254phenyl]-4,5-dihydro-1H-imidazole; HBr hydrobromide Y2-[2-(2-Methoxy-5-nitro-benzyloxy)- C₁₈H₁₉N₃O₄ 341.14 342.1 220-221phenyl]-1,4,5,6-tetrahydro-pyrimidine; HCl hydrochloride AA2-[2-(2-Bromo-benzylsulfanyl)-phenyl]- C₁₇H₁₇BrN₂S 360.03 361.0 177-1791,4,5,6-tetrahydro-pyrimidine; HBr (rel. hydrobromide int. = 96 P2-[2-(3-Iodo-benzylsulfanyl)-phenyl]- C₁₇H₁₇IN₂S 408.02 409 183-1851,4,5,6-tetrahydro-pyrimidine; HBr hydrobromide AG2-[2-(2-Methoxy-5-nitro-benzylsulfanyl)- C₂₁H₂₃N₃O₃S 397.15 398.1 >240phenyl]-3a,4,5,6,7,7a-hexahydro-1H- HBr benzoimidazole; hydrobromide AL2-[2-(2-Methoxy-napthalen-1- C₂₂H₂₂N₂OS 362.1 363ylmethylsulfanyl)-phenyl]-1,4,5,6- HCl tetrahydropyrimidine;hydrochloride AM 2-[2-(5-bromo-2-methoxy-benzylsulfanyl)- C₁₈H₁₉BrN₂OS390 390.9 phenyl]-1,4,5,6-tetrahydropyrimidine; HCl hydrochloride

[1796] The compounds given in Table 1, were made using proceduressimilar to that used for Compound IZ. The ES-LRMS values each had arelative intensity of 100.

[1797] The compounds given in Table 6, were made using generalprocedures similar to those used for Compounds TB, AAP, ZF, ZP, ZQ, ABB,ABC, ZM. For example:

[1798] a similar procedure can be used to couple a variety ofhalomethylaryls to substituted or unsubstituted aryl carbonitriles asthat used in scheme 5 or 18 above;

[1799] a similar procedure can be used to couple a variety ofbromomethyl- or chloromethyl-aryls to substituted or unsubstituted arylcarboxylic acids as that used in scheme 21 above,

[1800] a variety of substituted ethylenediamines can be synthesizedusing a similar procedure to that of scheme 26;

[1801] by utilizing ethanolamines containing substituents on either orboth carbons in the first step and other primary amines in the secondstep, a variety of amidines can be prepared using a similar procedure tothat of scheme 27;

[1802] amidines can be synthesized using substituted acrylonitriles in asimilar procedure to that of scheme 28;

[1803] substituted thiazoles can be prepared using a similar procedureto scheme 30 with a substituted imidazolidinethione; and

[1804] other analogs can be prepared by the general procedure of scheme33 using a variety of alkylchlorides in the final step.

[1805] Similar synthetic methods are designated according to the schemesdepicted in examples above. TABLE 6 Physical Data of Selected MC4-RBinding Compounds LCMS Mol m/z Synthetic ID Chemical Name Weightobserved Methods PZ 5,5-Dimethyl-2-[2-(2- 328.4564 329 18, 26naphthalen-1-yl-ethyl)- phenyl]-4,5-dihydro-1H- imidazole QA2-[3-Fluoro-2-(2-naphthalen- 346.4469 347 18, 261-yl-ethyl)-phenyl]-5,5- dimethyl-4,5-dihydro-1H- imidazole RD2-{2-[2-(5-Bromo-2-methoxy- 387.3195 387.16 18, 26phenyl)-ethyl]-3-methyl- phenyl}-5-methyl-4,5- dihydro-1H-imidazole RG2-{2-[2-(5-Bromo-2-methoxy- 421.7637 421.21 18, 26phenyl)-ethyl]-3-chloro- phenyl}-4,4-dimethyl-4,5- dihydro-1H-imidazoleSJ 2-{2-[2-(5-Bromo-2-methoxy- 407.7374 N/A 18, 26phenyl)-ethyl]-3-chloro- phenyl}-1-methyl-4,5- dihydro-1H-imidazole TB2-{2-[2-(5-Bromo-2-methoxy- 393.7105 394.66 18, 26phenyl)-ethyl]-3-chloro- phenyl}-4,5-dihydro-1H- imidazole TS2-{2-[2-(5-Bromo-2-methoxy- 421.7643 421 18, 26 phenyl)-ethyl]-3-chloro-phenyl}-1-ethyl-4,5-dihydro- 1H-imidazole UH2-[3-Chloro-2-(2-naphthalen- 334.848 335.06 18, 261-yl-ethyl)-phenyl]-4,5- dihydro-1H-imidazole US2-{2-[2-(5-Bromo-2-methoxy- 379.3207 378.82 18, 26phenyl)-ethyl]-thiophen-3-yl}- 1-methyl-4,5-dihydro-1H- imidazole UZ2-{2-[2-(5-Bromo-2-methoxy- 447.8021 446.95 7, 8, 9, 25phenyl)-ethyl]-3-chloro- 21, 27 phenyl}-3a,4,5,6,7,7a- hexahydro-1H-benzoimidazole VF 2-[3-Chloro-2-(2-naphthalen- 348.8749 349.06 18, 261-yl-ethyl)-phenyl]-1-methyl- 4,5-dihydro-1H-imidazole WL2-[2-(2-Benzofuran-7-yl- 290.3648 291.1 18, 26ethyl)-phenyl]-4,5-dihydro- 1H-imidazole WM 2-[2-(2-Naphthalen-1-yl-300.433 301.12 18, 26 ethyl)-phenyl]-4,5-dihydro- 1H-imidazole WN2-[2-(2-Benzofuran-7-yl- 308.3553 309.09 18, 26ethyl)-3-fluoro-phenyl]-4,5- dihydro-1H-imidazole WO1-Methyl-2-[2-(2-naphthalen- 314.4302 315.25 18, 261-yl-ethyl)-phenyl]-4,5- dihydro-1H-imidazole WP 2-{2-[2-(2-Methyl-314.4302 315.16 18, 26 naphthalen-1-yl)- ethyl]-phenyl}-4,5-dihydro-1H-imidazole WQ 2-{2-[2-(5-Chloro-2-methoxy- 314.8411 315.19 18,26 phenyl)-ethyl]-phenyl}-4,5- dihydro-1H-imidazole WR2-[3-Fluoro-2-(2-naphthalen- 318.3937 319.13 18, 261-yl-ethyl)-phenyl]-4,5- dihydro-1H-imidazole WS 2-{2-[2-(2,5-Dichloro-319.2329 319.01 18, 26 phenyl)-ethyl]-phenyl}- 4,5-dihydro-1H-imidazoleWT 2-[2-(2-Benzo[b]thiophen-4- 324.4219 325.12 18, 26yl-ethyl)-3-fluoro-phenyl]-4,5- dihydro-1H-imidazole WU1-Ethyl-2-[2-(2-naphthalen-1- 328.457 329 18, 26yl-ethyl)-phenyl]-4,5-dihydro- 1H-imidazole WV 2-[2-(2-Benzo[1,3]dioxol-328.798 329.11 18, 26 4-yl-ethyl)-3-chloro- phenyl]-4,5-dihydro-1H-imidazole WX 2-{2-[2-(2-Methoxy- 330.4296 331.11 18, 26naphthalen-1-yl)-ethyl]- phenyl}-4,5-dihydro-1H- imidazole WY2-{3-Chloro-2-[2-(4-fluoro- 352.8385 353.15 18, 26naphthalen-1-yl)-ethyl]- phenyl}-4,5-dihydro-1H- imidazole WZ2-{2-[2-(2,3,5-Trichloro- 353.6777 353.05 18, 26phenyl)-ethyl]-phenyl}-4,5- dihydro-1H-imidazole XA3-[2-(2-Naphthalen-1-yl- 354.4949 355.15 18, 26ethyl)-phenyl]-1,5,6,7,8,8a- hexahydro-imidazo[1,5- a]pyridine XB2-{2-[2-(5-Bromo-2-methoxy- 359.2657 359.98 18, 26phenyl)-ethyl]-phenyl}-4,5- dihydro-1H-imidazole XC2-{2-[2-(2-Bromo-5-chloro- 363.6842 N/A 18, 26phenyl)-ethyl]-phenyl}-4,5- dihydro-1H-imidazole XD2-{2-[2-(5-Bromo-2-chloro- 363.6842 363.73 18, 26phenyl)-ethyl]-phenyl}-4,5- dihydro-1H-imidazole XE2-{3-Fluoro-2-[2-(2-methoxy- 366.3584 367.27 18, 265-trifluoromethyl-phenyl)- ethyl]-phenyl}-4,5-dihydro- 1H-imidazole XF2-{2-[2-(2-Methyl- 368.5218 369.09 18, 26 naphthalen-1-yl)-ethyl]-phenyl}-3a,4,5,6,7,7a- hexahydro-1H- benzoimidazole XG 2-{2-[2-(5-Bromo-369.2609 369.07 18, 26 benzofuran-7-yl)-ethyl]- phenyl)-4,5-dihydro-1H-imidazole XH 2-{2-[2-(5-Bromo-2,3- 371.2767 372.99 18, 26dihydro-benzofuran-7-yl)- ethyl]-phenyl}-4,5-dihydro- 1H-imidazole XJ2-{2-[2-(6-Bromo- 373.2493 373.11 18, 26 benzo[1,3]dioxol-4-yl)-ethyl]-phenyl}-4,5-dihydro-1H- imidazole XK 2-{2-[2-(5-Bromo-2-methoxy-373.2926 375.97 18, 26 phenyl)-ethyl]-phenyl}-1- methyl-4,5-dihydro-1H-imidazole XL 3-[3-Chloro-2-(2-naphthalen- 374.9128 375.09 18, 261-yl-ethyl)-phenyl]-5,6,7,7a- tetrahydro-1H-pyrrolo[1,2- c]imidazole XM2-{2-[2-(5-Bromo-2-methoxy- 377.2562 377.11 18, 26phenyl)-ethyl]-3-fluoro- phenyl}-4,5-dihydro-1H- imidazole XN2-{2-[2-(3-Bromo-naphthalen- 379.2993 378.82 18, 261-yl)-ethyl]-phenyl}-4,5- dihydro-1H-imidazole XO2-{2-[2-(2-Bromo-5-chloro- 381.6747 380.93 18, 26phenyl)-ethyl]-3-fluoro- phenyl}-4,5-dihydro-1H- imidazole XP2-{2-[2-(5-Bromo-2-chloro- 381.6747 380.93 18, 26phenyl)-ethyl]-3-fluoro- phenyl}-4,5-dihydro-1H- imidazole XQ2-{2-[2-(5-Bromo-2-methyl- 383.2877 383.09 18, 26benzofuran-7-yl)-ethyl]- phenyl}-4,5-dihydro-1H- imidazole XR2-{2-[2-(2-Methoxy- 384.5212 385.22 18, 26 naphthalen-1-yl)-ethyl]-phenyl}-3a,4,5,6,7,7a- hexahydro-1H- benzoimidazole XS 2-{2-[2-(5-Bromo-385.3275 385.14 18, 26 benzo[b]thiophen-7-yl)-ethyl]-phenyl}-4,5-dihydro-1H- imidazole XT 2-{2-[2-(5-Bromo- 387.2513 388.9818, 26 benzofuran-7-yl)-ethyl]-3- fluoro-phenyl}-4,5-dihydro-1H-imidazole XU 2-{2-[2-(5-Bromo-2-methoxy- 387.3195 388.9918, 26 phenyl)-ethyl]-phenyl}-1- ethyl-4,5-dihydro-1H- imidazole XW2-[3-Chloro-2-(2-naphthalen- 388.9397 389.13 18, 26 1-yl-ethyl)-phenyl]-3a,4,5,6,7,7a-hexahydro-1H- benzoimidazole XY3-[3-Chloro-2-(2-naphthalen- 388.9397 389.11 18, 26 1-yl-ethyl)-phenyl]-1,5,6,7,8,8a-hexahydro- imidazo[1,5-a]pyridine XZ 2-{2-[2-(6-Bromo-391.2397 392.91 18, 26 benzo[1,3]dioxol-4-yl)-ethyl]-3-fluoro-phenyl}-4,5-dihydro- 1H-imidazole YA2-{2-[2-(5-Bromo-2-methoxy- 391.2831 391.26 18, 26phenyl)-ethyl]-3-fluoro- phenyl}-1-methyl- 4,5-dihydro-1H-imidazole YB2-{2-[2-(3-Bromo-naphthalen- 397.2898 396.77 18, 261-yl)-ethyl]-3-fluoro-phenyl}- 4,5-dihydro-1H-imidazole YC2-{2-[2-(5-Bromo-2,3- 397.3146 397.07 18, 26 dimethyl-benzofuran-7-yl)-ethyl]-phenyl}-4,5-dihydro- 1H-imidazole YD 2-{2-[2-(5-Bromo- 403.3179402.96 18, 26 benzo[b]thiophen-7-yl)-ethyl]-3-fluoro-phenyl}-4,5-dihydro- 1H-imidazole YE2-{2-[2-(5-Bromo-2-methoxy- 403.3189 403.1 18, 26phenyl)-ethyl]-3-ethoxy- phenyl}-4,5-dihydro-1H- imidazole YF2-{2-[2-(5-Bromo-2-methoxy- 403.3189 404.93 18, 26phenyl)-ethyl]-3-methoxy- phenyl}-1-methyl- 4,5-dihydro-1H-imidazole YG2-{2-[2-(5-Bromo- 403.7056 404.96 18, 26 benzofuran-7-yl)-ethyl]-3-chloro-phenyl}- 4,5-dihydro-1H-imidazole YH 2-{2-[2-(5-Bromo-2-methoxy-405.31 N/A 18, 26 phenyl)-ethyl]-3-fluoro- phenyl}-1-ethyl-4,5-dihydro-1H-imidazole YI 2-{2-[2-(5-Bromo-2-methoxy- 405.31 405.18 18, 26phenyl)-ethyl]-3-fluoro- phenyl}-5,5-dimethyl-4,5- dihydro-1H-imidazoleYJ 2-{2-[2-(6-Bromo- 407.694 406.95 18, 26benzo[1,3]dioxol-4-yl)-ethyl]- 3-chloro-phenyl}-4,5-dihydro-1H-imidazole YK 2-{2-[2-(2,5-Dibromo- 408.1355 407.07 18, 26phenyl)-ethyl]-phenyl}-4,5- dihydro-1H-imidazole YL 2-{2-[2-(5-Bromo-413.314 415.1 18, 26 benzofuran-7-yl)-ethyl]- 3-ethoxy-phenyl}-4,5-dihydro-1H-imidazole YM 3-{2-[2-(5-Bromo-2-methoxy- 413.3547 415.118, 26 phenyl)-ethyl]-phenyl}- 1,5,6,7,8,8a-hexahydro-imidazo[1,5-a]pyridine YN 2-{2-[2-(3-Bromo-naphthalen- 413.7441 412.6918, 26 1-yl)-ethyl]-3-chloro-phenyl}- 4,5-dihydro-1H-imidazole YO2-{2-[2-(8-Bromo-naphthalen- 413.7441 413.38 18, 261-yl)-ethyl]-3-chloro-phenyl}- 4,5-dihydro-1H-imidazole YP2-{2-[2-(5-Bromo-2-methoxy- 417.3458 418.93 18, 26phenyl)-ethyl]-3-ethoxy- phenyl}-1-methyl- 4,5-dihydro-1H-imidazole YQ2-{2-[2-(2,5-Dibromo- 426.126 424.92 18, 26 phenyl)-ethyl]-3-fluoro-phenyl}-4,5-dihydro-1H- imidazole YR 2-{2-[2-(5-Bromo-2- 431.2276 430.7618, 26 trifluoromethoxy-phenyl)- ethyl]-3-fluoro-phenyl}-4,5-dihydro-1H-imidazole YS 2-{2-[2-(5-Bromo-2- 431.2371 412.73 18, 26trifluoromethoxy-phenyl)- ethyl]-phenyl}-4,5-dihydro- 1H-imidazole YT3-{2-[2-(5-Bromo-2-methoxy- 431.3478 431.1 18, 26phenyl)-ethyl]-3-fluoro- phenyl}-1,5,6,7,8,8a- hexahydro-imidazo[1,5-a]pyridine YU 2-{2-[2-(5-Bromo-2-methoxy- 431.3727 430.97 18, 26phenyl)-ethyl]-3-ethoxy- phenyl}-1-ethyl-4,5-dihydro- 1H-imidazole YV3-{2-[2-(5-Bromo-2-methoxy- 433.7753 432.88 18, 26phenyl)-ethyl]-3-chloro- phenyl}-5,6,7,7a-tetrahydro-1H-pyrrolo[1,2-c]imidazole YW 2-{2-[2-(6-Bromo-2-methoxy- 443.7704443.54 18, 26 naphthalen-1-yl)-ethyl]-3- chloro-phenyl}-4,5-dihydro-1H-imidazole YX 2-{2-[2-(5-Bromo-2- 447.6819 446.75 18, 26trifluoromethoxy-phenyl)- ethyl]-3-chloro-phenyl}-4,5-dihydro-1H-imidazole YY 2-{2-[2-(5-Bromo-2-methoxy- 447.8021 449.12 18,26 phenyl)-ethyl]-3-chloro- phenyl}-3a,4,5,6,7,7a- hexahydro-1H-benzoimidazole YZ 3-{2-[2-(5-Bromo-2-methoxy- 447.8021 446.87 18, 26phenyl)-ethyl]-3-chloro- phenyl}-1,5,6,7,8,8a- hexahydro-imidazo[1,5-a]pyridine ZA 2-{2-[2-(2,5-Dibromo- 466.1474 466.99 18, 26benzofuran-7-yl)-ethyl]-3- fluoro-phenyl}-4,5-dihydro- 1H-imidazole ZB2-{2-[2-(5-Bromo-2-methoxy- 469.8083 468.92 18, 26phenyl)-ethyl]-3-chloro- phenyl}-1-phenyl- 4,5-dihydro-1H-imidazole ZC2-{2-[2-(4-Bromo-3′-chloro- 474.2267 473.68 18, 26biphenyl-2-yl)-ethyl]- 3-chloro-phenyl}- 4,5-dihydro-1H-imidazole ZD3-{2-[2-(2-Naphthalen-1-yl- 381.5206 382.37 18, 26,ethyl)-phenyl]-4,5-dihydro- 28 imidazol-1-yl}-pentanenitrile ZE3-Methoxy-3-{2-[2-(2- 383.4931 384.11 18, 26, naphthalen-1-yl-ethyl)- 28phenyl]-4,5-dihydro-imidazol- 1-yl}-propionitrile ZF3-(2-{2-[2-(5-Bromo-2- 446.7741 446.02 18, 26, methoxy-phenyl)-ethyl]-3-28 chloro-phenyl}-4,5-dihydro- imidazol-1-yl)-propionitrile ZG3-(2-{2-[2-(5-Bromo-2- 460.8009 460.06 18, 26, methoxy-phenyl)-ethyl]-3-28 chloro-phenyl}-4,5-dihydro- imidazol-1-yl)-2-methyl- propionitrile ZH3-(2-{2-[2-(5-Bromo-2- 460.8009 459.99 18, 26, methoxy-phenyl)-ethyl]-3-28 chloro-phenyl}-4,5-dihydro- imidazol-1-yl)-butyronitrile ZI3-(2-{2-[2-(5-Bromo-2- 474.8278 474 18, 26, methoxy-phenyl)-ethyl]-3- 28chloro-phenyl}-4,5-dihydro- imidazol-1-yl)-pentanenitrile ZJ3-(2-{2-[2-(5-Bromo-2- 476.8003 475.97 18, 26, methoxy-phenyl)-ethyl]-3-28 chloro-phenyl}-4,5-dihydro- imidazol-1-yl)-3-methoxy- propionitrileZK 2-(1-{2-[2-(4,5-Dihydro-1H- 377.4616 N/A 18, 26,imidazol-2-yl)-6-fluoro- 33 phenyl]-ethyl}-naphthalen-2-yloxy)-ethylamine ZL 2-(3-Fluoro-2-{2-[2-(3- 404.5275 405.16 18, 26,methyl-butoxy)-naphthalen-1- 33 yl]-ethyl}-phenyl)-4,5-dihydro-1H-imidazole ZM [2-(1-{2-[2-(4,5-Dihydro-1H- 405.5153 406.14 18,26, imidazol-2-yl)-6-fluoro- 33 phenyl]-ethyl}-naphthalen-2-yloxy)-ethyl]-dimethyl-amine ZN [3-(1-{2-[2-(4,5-Dihydro-1H- 419.5422N/A 18, 26, imidazol-2-yl)-6-fluoro- 33 phenyl]-ethyl}-naphthalen-2-yloxy)-propyl]-dimethyl- amine ZO 4-[2-(1-{2-[2-(4,5-Dihydro- 447.5526N/A 18, 26, 1H-imidazol-2-yl)-6-fluoro- 33 phenyl]-ethyl}-naphthalen-2-yloxy)-ethyl]-morpholine ZP {2-[2-(5-Bromo-2-methoxy- 422.7521 422 18,29 phenyl)-ethyl]-3-chloro- benzyl}-(4,5-dihydro-1H-imidazol-2-yl)-amine ZQ 3-{2-[2-(5-Bromo-2-methoxy- 449.7985 449.25 18,30 phenyl)-ethyl]-3-chloro- phenyl}-5,6-dihydro- imidazo[2,1-b]thiazoleZR 3-{2-[2-(5-Bromo-2-methoxy- 477.8523 477.27 18, 30phenyl)-ethyl]-3-chloro- phenyl}-6,6-dimethyl-5,6- dihydro-imidazo[2,1-b]thiazole ZS 2-{2-[2-(5-Bromo-2- 429.6914 431.01 19, 26difluoromethoxy-phenyl)- ethyl]-3-chloro-phenyl}-4,5-dihydro-1H-imidazole ZT 2-(4,5-Dihydro-1H-imidazol- 301.3911 302.16 20,26 2-yl)-3-(2-naphthalen-1-yl- ethyl)-pyridine UR (2-{2-[2-(5-Bromo-2-432.7472 432.03 21, 27 methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro- imidazol-1-yl)-acetonitrile UY2-{2-[2-(5-Bromo-2-methoxy- 435.7911 434.73 21, 27phenyl)-ethyl]-3-chloro- phenyl}-1-propyl-4,5-dihydro- 1H-imidazole VG1-Benzyl-2-{2-[2-(5-bromo-2- 483.8351 484.91 21, 27methoxy-phenyl)-ethyl]-3- chloro-phenyl}-4,5-dihydro- 1H-imidazole VI2-{2-[2-(5-Bromo-2-methoxy- 435.7911 435.55 21, 27phenyl)-ethyl]-3-chloro- phenyl}-1-isopropyl-4,5- dihydro-1H-imidazoleVJ 2-{2-[2-(5-Bromo-2-methoxy- 475.7356 475 21, 27phenyl)-ethyl]-3-chloro- phenyl}-1-(2,2,2-trifluoro-ethyl)-4,5-dihydro-1H- imidazole ZU 4-Chloro-3-{2-[2-(4,5- 327.7884327.76 21, 27 dihydro-1H-imidazol-2-yl)-6- fluoro-phenyl]-ethyl}-benzonitrile ZV 7-{2-[2-(4,5-Dihydro-1H- 333.3651 334.15 21, 27imidazol-2-yl)-6-fluoro- phenyl]-ethyl}-benzofuran-5- carbonitrile ZW3-{2-[2-Chloro-6-(4,5- 339.8242 340.55 21, 27 dihydro-1H-imidazol-2-yl)-phenyl]-ethyl}-4-methoxy- benzonitrile ZX 2-(1-Isopropyl-4,5-dihydro-343.4717 344.24 21, 27 1H-imidazol-2-yl)-3-(2- naphthalen-1-yl-ethyl)-pyridine ZY 7-{2-[2-Chloro-6-(4,5- 349.8194 350.13 21, 27dihydro-1H-imidazol-2-yl)- phenyl]-ethyl}-benzofuran-5- carbonitrile ZZ(2-{2-[2-(2-Methyl- 353.4668 354.18 21, 27 naphthalen-1-yl)-ethyl]-phenyl}-4,5-dihydro- imidazol-1-yl)-acetonitrile AAA(2-{2-[2-(2-Methoxy- 369.4662 370.18 21, 27 naphthalen-1-yl)-ethyl]-phenyl}-4,5-dihydro- imidazol-1-yl)-acetonitrile AAB2-{2-[2-(5-Bromo-2-methoxy- 373.2926 375.14 21, 27phenyl)-ethyl]-6-methyl- phenyl}-4,5-dihydro-1H- imidazole AAC{2-[3-Chloro-2-(2-naphthalen- 373.8847 373.79 21, 271-yl-ethyl)-phenyl]-4,5- dihydro-imidazol-1-yl}- acetonitrile AAD2-[3-Chloro-2-(2-naphthalen- 376.9287 377.2 21, 271-yl-ethyl)-phenyl]-1-propyl- 4,5-dihydro-1H-imidazole AAE2-{2-[2-(5-Bromo-2-methoxy- 387.3195 387.25 21, 27phenyl)-ethyl]-phenyl}-1,5- dimethyl-4,5-dihydro-1H- imidazole AAF2-{2-[2-(5-Bromo-2-methoxy- 387.3195 387.16 21, 27phenyl)-ethyl]-phenyl}-1,4- dimethyl-4,5-dihydro-1H- imidazole AAG2-{2-[2-(5-Bromo-2-methoxy- 389.292 388.79 21, 27phenyl)-ethyl]-6-methoxy- phenyl}-4,5-dihydro-1H- imidazole AAH2-{2-[2-(5-Bromo-2-methoxy- 391.2831 393.03 21, 27phenyl)-ethyl]-3-fluoro- phenyl}-5-methyl- 4,5-dihydro-1H-imidazole AAI2-{2-[2-(5-Bromo-2-methoxy- 401.3464 401.25 21, 27phenyl)-ethyl]-phenyl}-5- ethyl-1-methyl-4,5- dihydro-1H-imidazole AAJ2-{2-[2-(5-Bromo-2-methoxy- 401.3464 401.21 21, 27phenyl)-ethyl]-phenyl}-1,4,5- trimethyl-4,5-dihydro-1H- imidazole AAK2-{2-[2-(5-Bromo-2-methoxy- 401.3464 401.23 21, 27phenyl)-ethyl]-phenyl}-4- ethyl-1-methyl-4,5-dihydro- 1H-imidazole AAL2-{2-[2-(5-Bromo-2-methoxy- 407.3745 409.05 21, 27phenyl)-ethyl]-thiophen-3-yl}- 1-propyl-4,5-dihydro-1H- imidazole AAM2-{2-[2-(5-Bromo-2-methoxy- 407.3745 409.05 21, 27phenyl)-ethyl]-thiophen-3-yl}- 1-isopropyl-4,5-dihydro-1H- imidazole AAN2-{2-[2-(5-Bromo-2-methoxy- 415.3733 415.3 21, 27phenyl)-ethyl]-phenyl}-4- isopropyl-1-methyl-4,5- dihydro-1H-imidazoleAAO 3-(2-{2-[2-(5-Bromo-2- 418.3574 420.06 21, 27methoxy-phenyl)-ethyl]- thiophen-3-yl}-4,5-dihydro-imidazol-1-yl)-propionitrile AAP 2-{2-[2-(5-Bromo-2-methoxy- 419.3368419.17 21, 27 phenyl)-ethyl]-3-fluoro- phenyl}-1-isopropyl-4,5-dihydro-1H-imidazole AAQ 2-{2-[2-(5-Bromo-2-methoxy- 423.3004 423.25 21,27 phenyl)-ethyl]-3-fluoro- phenyl}-1-(2-fluoro-ethyl)-4,5-dihydro-1H-imidazole AAR 2-{2-[2-(5-Bromo-2-methoxy- 433.3637 433.2921, 27 phenyl)-ethyl]-3-fluoro- phenyl}-1-butyl-4,5-dihydro-1H-imidazole AAS 2-(2-{2-[2-(5-Bromo-2- 446.7741 447.87 21, 27methoxy-phenyl)-ethyl]-3- chloro-phenyl}-4,5-dihydro-imidazol-1-yl)-propionitrile AAT 2-{2-[2-(5-Bromo-2-methoxy- 459.2814459.13 21, 27 phenyl)-ethyl]-3-fluoro- phenyl}-1-(2,2,2-trifluoro-ethyl)-4,5-dihydro-1H- imidazole AAU 2-{2-[2-(5-Bromo-2-methoxy-474.4163 474.29 21, 27 phenyl)-ethyl]-3-fluoro-phenyl}-1-(2-pyrrolidin-1-yl- ethyl)-4,5-dihydro-1H- imidazole AAV2-{2-[2-(5-Bromo-2-methoxy- 488.4432 488.35 21, 27phenyl)-ethyl]-3-fluoro- phenyl}-1-(3-pyrrolidin-1-yl-propyl)-4,5-dihydro-1H- imidazole AAW 2-{2-[2-(5-Bromo-2-methoxy-489.8828 491.09 21, 27 phenyl)-ethyl]-3-chloro- phenyl}-1-propyl- 3a,4,5,6,7,7a-hexahydro-1H- benzoimidazole AAX [3-(2-{2-[2-(5-Bromo-2- 490.459490.32 21, 27 methoxy-phenyl)-ethyl]-3- fluoro-phenyl}-4,5-dihydro-imidazol-1-yl)-propyl]- diethyl-amine AAY 4-[3-(2-{2-[2-(5-Bromo-2-504.4426 504.37 21, 27 methoxy-phenyl)-ethyl]-3-fluoro-phenyl}-4,5-dihydro- imidazol-1-yl)-propyl]- morpholine AAZ1-[3-(2-{2-[2-(5-Bromo-2- 517.4847 517.38 21, 27methoxy-phenyl)-ethyl]-3- fluoro-phenyl}-4,5-dihydro-imidazol-1-yl)-propyl]-4- methyl-piperazine ABA [4-(2-{2-[2-(5-Bromo-2-534.9671 534.13 21, 27 methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro- imidazol-1-yl)-pentyl]-diethyl- amine ABB(2-{2-[2-(5-Bromo-2- 451.7472 453.03 21, 27, methoxy-phenyl)-ethyl]-3-32 chloro-phenyl}-4,5-dihydro- imidazol-1-yl)-acetic acid ABC(2-{2-[2-(5-Bromo-2- 403.3189 403.15 21, 27, methoxy-phenyl)-ethyl]- 32phenyl}-3-methyl- 4,5-dihydro-3H-imidazol- 4-yl)-methanol ABD2-{2-[2-(5-Bromo-2-methoxy- 393.7105 392.93 21, 27,phenyl)-ethyl]-6-chloro- 33 phenyl}-4,5-dihydro-1H- imidazole

EXAMPLE 4 Scincillation Proximity Assay (SPA)

[1806] High-Throughput Receptor Binding Screening for MC4-R BindingCompounds

[1807] A. Preparation of Membranes from MC4-R Cells

[1808] A crude preparation of plasma membranes, of sufficient purity foruse in the scintillation proximity assay (SPA), was prepared using thefollowing protocol (Maeda et al. (1983) Biochem. Biophys. Acta731:115-120).

[1809] MC4-R cells were stable recombinant K293 cells overexpressing theMC4-R. The cells were routinely cultured and passaged in a growth mediumcomposed of DMEM base medium: 10% fetal bovine serum (FBS), 1×Glutamine, and 0.5 mg/ml G418. Terminal cultures (i.e., those which willbe processed to produce plasma membranes) were grown in identical media,with the exception that the media contained 0.2 mg/ml G418.

[1810] At 4° C., harvested cells were pelleted and immediately washedwith 25 mL of PBS. The washed cells were resuspended in two volumes ofSTM buffer (0.25 M sucrose, 5 mM Tn's, 1 mM MgCl₂, pH 7.5), containingBoehringer Complete™ protease inhibitors. Cell breakage was accomplishedusing a Dounce homogenizer. After 20-30 strokes, nuclei and unbrokencells were pelleted by centrifugation at 1100 rpm for 5 minutes. Thesupernatant was saved and the pellet was resuspended in 1 volume ofSTM/protease inhibitors, and then a further lysis step was carried outby the Dounce homogenizer (10-20 strokes). This material was thencombined with the first supernatant. 11.25 mL of the homogenate wasgently layered on top of 27.25 mL f 42% (w/w) sucrose (5 mM Tris, 1 mMMgCl₂, pH 7.5). After spinning at 28,000 rpm (ultracentrifuge, SW-28rotor) for 90 minutes, membranes were collected at the interface with atransfer pipette.

[1811] The membrane suspension obtained from the sucrose interface wascollected and diluted with 5 mM Tris and 1 mM MgCl₂. Membranes werecollected by a further round of centrifugation at 33,000 rpm for 30minutes (SW-41 Ti rotor). The pellet of membranes was subsequentlyresuspended in a small (0.5 mL) volume of STM, using a 2 mL Douncehomogenizer, and immediately frozen. The resulting membranes were stableto both freeze-thaw cycles and temperatures around 4° C. for at least 6hours.

[1812] B. High-Throughput Screen

[1813] A scincillation proximity assay (SPA) format ligand binding assaywas used. The membranes from the MC4-R mammalian cells (K293 expressingMC4-R) were bound to wheat germ agglutinin (WGA) coated SPA beads. Themembrane coated SPA beads were added to screening plates, whichcontained the test compounds pre-dissolved in 30 μL of 10% DMSO. Afterpre-equilibration of the receptor coated beads with the test compounds(1 hour), 2 nM of radioactive ligand ([¹²⁵I]NDP-α-MSH) was added. Sincethe binding of the radioactive ligand to the receptor causes thescincillation of the beads, blockage of the binding of the radioactiveligand by a small molecule causes a reduction in scincillation.

[1814] 1. Pre-Binding of the MC4R Membranes to the WGA-SPA Beads

[1815] The membranes were mixed with the SPA beads to make a 2× stock ofmembrane and beads.

[1816] For a twenty plate batch of screening plates, the components weremixed in proportions given in Table 2. The membranes and beads werestirred with a magnetic stir bar at room temperature for 1-2 hours toallow binding. TABLE 2 Final Component Volume Concentration in Assay 4mg/ml WGA-SPA Beads 14.4 mL 25 μg/well MC4R crude plasma membranes*  600μL*  5 μg/well SPA Binding Buffer  100 mL N/A

[1817] 2. Binding Assay

[1818] The following assay was performed with automation using aTitertec MultiDrop with plate stacker.

[1819] 30 μL of 10% DMSO was added per well to the dried compound filmin an OptiPlate. Then, 5 μL of cold NDP-α-MSH was added to the controlwells. Subsequently, 50 μl per well of 2× membranes and beads were addedand pre-equilibrated with the compounds for 1 hour.

[1820] Binding was initiated by adding 20 μL of radioactive ligand (a 20nM solution of [¹²⁵I]-NDP-α-MSH) to each test well. The plates wereincubated overnight at room temperature and read the following morning.

[1821] The reagents and amounts are summarized below in Table 3. TABLE 3Volume (μL) Reagent Max (100%) Min (0%) 50% Test 20% DMSO 30 30 30 30 2Xmembranes + beads 60 0 60 60 2nM [¹²⁵I]-NDP-α-MSH in 20 20 20 20 bindingbuffer NDP-α-MSH (5 μM in H₂O) 5 0 0  0 NDP-α-MSH (20 nM in H₂O) 0 0 5 0 Test Compound* 0 0 0 5 μM

[1822] Potency of inhibitors was quantified with respect to positive(100% inhibition) and negative (no inhibitor; 0% inhibition) controls.The following formula was used:

% Inhibition={1−[cpm−(positive control)]/[(negative control)−(positivecontrol)]}*100%

[1823] Results from the SPA, are summarized in Table 4. In Table 4, *indicates good inhibition of the MC4-R, ** indicates very goodinhibition of the MC4-R, and *** indicates exemplary inhibition of theMC4-R.

[1824] Compounds which were found to be not active as MC4-R bindingcompounds, using the SPA assay described herein, are depicted in Table5.

[1825] In an embodiment, the present invention pertains to the compoundsand methods described herein provided that the compound is not selectedfrom the group consisting of those depicted in Table 5. TABLE 4 MolWeight MC4-R ID CHEMICAL NAME (Tot) Structure Binding A2-[2-(2,5-Dichloro- thiophen-3- ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro- pyrimidine; HCl 393.7877

** B 2-[2-(2-Chloro-6-fluoro- benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro- pyrimidine; HCl 415.7566

** D 2-(2-Benzylsulfanyl- phenyl)-1,4,5,6- tetrahydro-pyrimidine; HBr363.3214

* E 2-(2-Pentadecylsulfanyl- phenyl)-1,4,5,6- tetrahydro-pyrimidine; HBr483.6

* F 2-(2-Cyclohexylmethylsulfanyl- phenyl)-1,4,5,6-tetrahydro-pyrimidine; HBr 369.369

* G 2-[2-(2-Methyl- benzylsulfanyl)-phenyl]- 1,4,5,6-tetrahydro-pyrimidine; HBr 377.3483

* H 2-[2-(3-Nitro- benzylsulfanyl)-phenyl]- 1,4,5,6-tetrahydro-pyrimidine; HBr 408.319

* I 2-[2-(4-Benzyloxy- benzylsulfanyl)-phenyl]- pyrimidine; HCl 424.9934

** M 2-[2-(2-Iodo- benzylsulfanyl)-phenyl]- 1,4,5,6-tetrahydro-pyrimidine; HCl 444.7659

** N 2-[2-(2-Methoxy-5-nitro- benzylsulfanyl)-phenyl)-1,4,5,6-tetrahydro- pyrimidine; HBr 438.3453

*** O 2-[2-(Naphthalen-1- ylmethylsulfanyl)-phenyl]- 1,4,5,6-tetrahydro-pyrimidine; HCl 368.9293

*** P 2-[2-(3-Iodo- benzylsulfanyl)-phenyl]- 1,4,5,6-tetrahydro-pyrimidine; HBr 489.2179

** Q 2-[2-(3-Chloro- benzylsulfanyl)-phenyl]- 1,4,5,6-tetrahydro-pyrimidine 397.7662

* R 2-[2-(3,5-Dimethoxy- benzylsulfanyl)-phenyl]- 1,4,5,6-tetrahydro-pyrimidine; HCl 378.922

** S 2-[2-(4-Fluoro- benzylsulfanyl)-phenyl]- 1,4,5,6-tetrahydro-pyrimidine; HBr 381.3119

* T 2-[2-(2-Chloro- benzylsulfanyl)-phenyl]- 1,4,5,6-tetrahydro-pyrimidine 397.7662

* U 2-[2-(2-Fluoro- benzylsulfanyl)-phenyl]- 1,4,5,6-tetrahydro-pyrimidine; HBr 381.3119

* V 2-[2-(2,4-Bis- trifluoromethyl- benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro- pyrimidine; HBr 499.3179

* W 2-[2-(3-Methoxy- benzylsulfanyl)-phenyl]- 1,4,5,6-tetrahydro-pyrimidine; HCl 348.8957

* X 2-[2-(3,5-Bis- trifluoromethyl- benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro- pyrimidine; HCl 454.8659

* Y 2-[2-(2-Methoxy-5-nitro- benzyloxy)-phenyl]- 1,4,5,6-tetrahydro-pyrimidine; HCl 377.8267

** Z 2-[2-(3-Bromo- benzylsulfanyl)-phenyl]- 1,4,5,6-tetrahydro-pyrimidine; HBr 442.2175

** AA 2-[2-(2-Bromo- benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine 442.2175

** AB 2-[2-(2-Chloro-6-fluoro- benzylsulfanyl)-phenyl]-4,5-dihydro-1H-imidazole 357.2777

* AC 2-(2-Benzylsulfanyl- phenyl)-4,5-dihydro-1H- imidazole; HCl304.8425

* AE 2-[2-(2-Iodo- benzylsulfanyl)-phenyl]- 4,5-dihydro-1H-imidazole;HCl 430.7391

** AF 2-[2-(2-Methoxy-5-nitro- benzylsulfanyl)-phenyl]-4,5-dihydro-1H-imidazole; HBr 424.3184

** AG 2-[2-(2-Methoxy-5-nitro- benzylsulfanyl)-phenyl]-3a,4,5,6,7,7a-hexahydro- 1H-benzoimidazole; HBr 478.41

*** AH 2-[2-(Naphthalen-1- ylmethoxy)-phenyl]- 1,4,5,6-tetrahydro-pyrimidine; Formate 362.4327

** AI 2-[2-(2,5-Dimethoxy- benzylsulfanyl)-phenyl]- 1,4,5,6-tetrahydro-pyrimidine; HCl 378.922

** AJ 2-[2-(2-Methyl- naphthalen-1- ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine 346.4962

*** AK 1-{2-[2-(2-Chloro-6-fluoro- benzylsulfanyl)-phenyl]-5,6-dihydro-4H-pyrimidin- 1-yl}-ethanone 376.8819

** AL 2-[2-(2-Methoxy- naphthalen-1- ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro- pyrimidine; HCl 398.9556

*** AM 2-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro- pyrimidine; HCl 427.7917

*** AN 1-(6-Bromo-2-chloro- quinolin-4-yl)-3-(2-diethylamino-ethyl)-urea 399.7179

* AO 2-[2-(2,6-Difluoro- benzylsulfanyl-phenyl]- 1,4,5,6-tetrahydro-pyrimidine; HBr 480.2143

* AP 10-[2-(1-Methyl-piperidin- 2-yl)-ethyl]-2- methylsulfanyl-10H-phenothiazine; HCl 407.0429

* AQ 4-(3,5-Bis-trifluoromethyl- phenyl)-1,4,6,7-tetrahydro-imidazo[4,5- c]pyridine-5-carbothioic acid(3-diethylamino-propyl)-amide 507.5465

* AR 1-(4-Hydroxy-1,3,5- trimethyl-piperidin-4-yl)- ethanone 185.2664

** AS 2-Naphthalen-1-ylmethyl- 4,5-dihydro-1H-imidazole; HCl 246.7386

* AT 1-(3-Diethylamino-propyl)-3-{1- [5-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-thiophene-2- sulfonyl]-pyrrolidin-3-yl}- thiourea552.7096

* AU N-[2-Cyclopropyl-3- (1,1,3,3-tetramethyl- butylamino)-imidazo[1,2-a]pyridin-8-yl]-acetamide 342.4846

* AV (2-Isopropyl-imidazo[1,2- a]pyridin-3-yl)-(1,1,3,3-tetramethyl-butyl)-amine 342.4846

* AW (2-Isopropyl-imidazo[1,2- a]pyridin-3-yl)-(1,1,3,3-tetramethyl-butyl)-amine 287.4485

* AX 1-(4-Phenyl-5′-trifluoromethyl- 3,4,5,6-tetrahydro-2H-[1,2′]-bipyridinyl-4-ylmethyl)-3-(2- piperidin-1-yl-ethyl)-thiourea 505.6509

* AY (2,6-Dichloro-phenyl)- imidazolidin-2-ylidene- amine; HCl 266.5561

* AZ 2-Benzyl-4,5-dihydro-1H- imidazole 160.2188

* BA 1-(4-Phenyl-5′- trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl- 4-ylmethyl)-3-(2-piperidin-1-yl-ethyl)-urea 489.5843

* BB 2-(2-Methylsulfanyl)- phenyl)-1,4,5,6-tetrahydro- pyrimidine334.2216

* BZ 2-(1,4,5,6-Tetrahydro- pyrimidin-2-yl)-benzenethiol 192.2848

* BD 2-[2-(4-Nitro- benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine 408.319

* BE 2-{3-[2-(1,4,5,6- Tetrahydro-pyrimidin-2- yl)-phenylsulfanyl]-propyl}-isoindole-1,3- dione; HBr 460.3948

* BF 2-[2-(3-Phenyl- propylsulfanyl)-phenyl]- 1,4,5,6-tetrahydro-pyrimidine; HBr 391.3752

* BG 2-[2-(4-Trifluoromethyl- benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro- pyrimidine; HBr 431.3197

* BH 4-Piperazin-1-yl-2- trifluoromethyl-quinoline 281.2806

* BI 3-Nitro-benzamidine; HCl 201.6116

* BJ 4-Carbamimidoyl- benzamide 163.1791

* BK 2-Phenyl-4,5-dihydro-1H- imidazole 146.1919

* BL 2-(3-Benzylsulfanyl- phenyl)-1,4,5,6-tetrahydro- pyrimidine282.4094

* BM 2-[2-(4-tert-Butyl- benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine; HBr 419.4289

* BN 2,2-Diphenyl-4-[2- (1,4,5,6-tetrahydro-pyrimidin-2-yl)-phenylsulfanyl]- butyronitrile; HBr 492.4827

* BO 2-[2-(3,4-Dimethyl- benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine; HCl 346.9232

* BQ 3-[2-(1,4,5,6-Tetrahydro- pyrimidin-2-yl)-phenylsulfanyl-methyl]-benzonitrile; HBr 388.3312

* BR 2-[2-(4-Bromo- benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine; HBr 442.2175

* BS 2-[2-(2,6-Dichloro- benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine; HBr 432.2109

* BT 2-[2-(Naphthalen-2- ylmethylsulfanyl)-phenyl]- 1,4,5,6-tetrahydro-pyrimidine; HBr 413.3813

* BU 2-[2-(4-Fluoro- benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine; HBr 381.3119

* BV 2-[2-(Biphenyl-4- ylmethylsulfanyl)-phenyl]- 1,4,5,6-tetrahydro-pyrimidine; HCl 394.9672

* BW 2-[2-(2,4-Bis- trifluoromethyl-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro- pyrimidine; HBr 499.3179

* BX 2-[2-(1,4,5,6-Tetrahydro- pyrimidin-2-yl)-phenylsulfanyl-methyl]-benzonitrile; HBr 388.3312

* BY 4-[2-(1,4,5,6-Tetrahydro- pyrimidin-2-yl)-phenylsulfanyl-methyl]-benzonitrile; HBr 388.3312

* BZ 2-[2-(4-Methoxy- benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine; HCl 348.8957

* CA Benzamidine; HCl 156.614

* CB 3,5-Bis-trifluoromethyl- benzamidine; HCl 292.6105

* CC 2-(2-Benzylsulfanyl- phenyl)-4,5-dihydro-1H- imidazole; HCl304.8425

* CD (2-Butoxy-phenyl)- carbamic acid 2-piperidin-1-yl-1-piperidin-1-ylmethyl- ethyl ester; Formate 463.6221

** CE (2-Pentyloxy-phenyl)- carbamic acid 2-piperidin-1-yl-1-piperidin-1-ylmethyl- ethyl ester; Formate 477.649

** CF 2-(2-Bromo-phenyl)-4,5- dihydro-1H-imidazole; HCl 261.5479

* CJ 4-Phenyl-2-piperazin-1-yl- 6-p-tolyl-pyrimidine 330.4326

* CK N-Benzyl-N-(3-chloro- benzyl)-N′,N′-dimethyl- ethane-1,2-diamine302.8468

* CL N-Benzyl-N-(4-bromo- benzyl)-N′,N′-dimethyl- ethane-1,2-diamine347.2981

* CM N-Benzyl-N-(3,4-dichloro- benzyl)-N′,N′-dimethyl-ethane-1,2-diamine 337.2916

* CO 7-Chloro-4,8-dimethyl-2- piperazin-1-yl-quinoline; Oxalate 365.8208

* CP 7-Chloro-4,8-dimethyl-2- piperazin-1-yl-quinoline 275.7808

* CQ 7-Chloro-4,8-dimethyl-2- piperazin-1-yl-quinoline; Formate 321.8108

* CS 2,7-Dichloro-4,8-dimethyl- quinoline 226.1046

* CT 2-(2-Benzylsulfanylphenyl)- 3a,4,5,6,7,7a-hexahydro-1H-benzoimidazole; HCl 358.9342

* CU 2-[2-(2-Chloro-6-fluoro- benzylsulfanyl)-phenyl]-3a,4,5,6,7,7a-hexahydro- 1H-benzoimidazole; HCl 411.3694

** CV 2-[2-(2-Iodo- benzylsulfanyl)-phenyl]- 3a,4,5,6,7,7a-hexahydro-1H-benzoimidazole; HCl 484.8307

** CY 1-Phenyl-3-piperazin-1-yl- 5,6,7,8-tetrahydro-isoquinoline-4-carbonitrile 318.4216

** CZ 2-[2-(Pyridin-3- ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine 283.3972

* DA 1-Pyridin-3-ylmethyl-2-[2- (pyridin-3- ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro- pyrimidine 374.5096

* DB 2-[2-(2-Ethoxy- ethylsulfanyl)-phenyl]- 1,4,5,6-tetrahydro-pyrimidine; HBr 345.3037

* DC 2-[2-(2,5-Dimethyl- benzylsulfanyl)-phenyl]- 1,4,5,6-tetrahydro-pyrimidine; HCl 346.9232

** DD 2-[-(2-Benzenesulfonylmethyl- benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro- pyrimidine; HBr 517.5108

* DE 4-[2-(1,4,5,6-Tetrahydro- pyrimidin-2-yl)- phenylsulfanylmethyl]-quinoline; HBr 414.3691

** DF 2-[2-(2-Methoxy-5-nitro- benzylsulfanyl)-pyridin-3-yl]-1,4,5,6-tetrahydro- pyrimidine; HBr 439.3331

** DG 2-[2-(2-Methoxy- benzylsulfanyl)-phenyl]- 1,4,5,6-tetrahydro-pyrimidine; HCl 348.8957

** DH 2-[2-(2-Cyclopentyloxy- benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro- pyrimidine; HBr 447.4393

** DI 2-Biphenyl-2-yl-1,4,5,6- tetrahydro-pyrimidine; Formate 282.3465

* DJ 2-[2-(2,3-Dimethoxy- benzylsulfanyl)-phenyl]- 1,4,5,6-tetrahydro-pyrimidine; HBr 423.374

* DK 2-[2-(2,3-Dihydro- benzo[1,4]dioxin-5- ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro- pyrimidine; HBr 421.3581

** DL 2-[2-(-6-Methoxy-2,3- dihydro-benzo[1,4]dioxin-5-ylmethylsulfanyl)-phenyl]- 1,4,5,6-tetrahydro-pyrimidine 451.3844

*** DM 2-[2-(5-fluoro-2-methoxy- benzylsulfanyl)-phenyl]-4,5-dihydro-1H-imidazole; HCl 411.3381

** DN 1-Methyl-2-[2- (naphthalen-1-ylmethyl- sulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine; formate 392.5262

** DO 1-Methyl-2-[2- (naphthalen-1-ylmethyl- sulfanyl)-phenyl]-4,5-dihydro-1H-imidazole 332.4693

*** DP 2-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-phenyl]-4,5-dihydro-1H-imidazole; HCl 413.7649

*** DQ 2-[2-(5-Bromo-2-methoxy- benzyloxy)-phenyl]- 1,4,5,6-tetrahydro-pyrimidine; HCl 411.7251

*** DR 2-[2-(Naphthalen-1- yloxymethyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine 316.4027

** DS 2-(2-Phenoxy-phenyl)- 1,4,5,6-tetrahydro- pyrimidine; HCl 288.7759

* DT 5-(4-Chloro-phenyl)-2,5- dihydro-3H-imidazo[2,1- a]isoindol-5-ol284.7448

* DU 2-[2-(2-Methoxy- phenoxymethyl)-phenyl]- 1,4,5,6-tetrahydro-pyrimidine; HCl 332.8291

* DV 2-[2-(2,6-Dimethoxy- phenoxymethyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine 326.3954

* DW 2-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-phenyl]-5,5-dimethyl-1,4,5,6- tetrahydro-pyrimidine 419.3855

*** DX 2-[2-(2-Methoxy- phenoxy)-phenyl]-1,4,5,6- tetrahydro-pyrimidine;Formate 328.3722

* DY 2-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-phenyl]-5,5-dimethyl-4,5-dihydro- 1H-imidazole 405.3586

*** DZ 2-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-5-trifluoromethyl-phenyl]- 1,4,5,6-tetrahydro- pyrimidine 459.33

* EA 2-[2-(2,6-Dimethoxy- benzylsulfanyl)-phenyl]- 1,4,5,6-tetrahydro-pyrimidine; HCl 378.922

*** EB 2-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-phenyl]-6-ethyl-1,4,5,6-tetrahydro- pyrimidine 419.3855

*** EC 2-(5-Bromo-2-methoxy- benzylsulfanyl)-benzonitrile 334.2364

* ED 2-[2-(2-Bromo-6-methoxy- benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro- pyrimidine; HBr 472.2437

*** EF 2-[5-Bromo-2-(5-bromo-2- methoxy-benzylsulfanyl)-phenyl]-4,5-dihydro-1H- imidazole; Formate 502.2309

*** EJ 9-Benzylidene-1,2,3,9- tetrahydro-4,9a-diaza- fluorene; Formate306.3685

* EK 2-[2-(Biphenyl-3-yloxy)- phenyl]-4,5-dihydro-1H- imidazole 314.3868

* EL 2-[2-(4-Chloro-phenoxy)- phenyl]-4,5-dihydro-1H- imidazole 272.7338

* EM 2-[5-Bromo-2-(5-bromo-2- methoxy-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro- pyrimidine; Formate 516.2578

*** EN 2-[2-(Naphthalen-2- yloxy)-phenyl]-4,5- dihydro-1H-imidazole;Formate 334.3789

* EO 2-[4-Bromo-2-(5-bromo-2- methoxy-benzylsulfanyl)- phenyl]-1,4,5,6-tetrahydro-pyrimidine 470.2278

** EP 2-[2-(2-Bromo-5-methoxy- benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro- pyrimidine; HBr 472.2437

*** EQ 2-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-5-methyl-phenyl]-1,4,5,6- tetrahydro-pyrimidine 405.3586

*** ER 2-[2-(Naphthalen-1- yloxy)-phenyl]-4,5-dihydro- 1H-imidazole;formate 334.3789

* ES 2-[2-(Naphthalen-1- yloxy)-phenyl]-1,4,5,6- tetrahydro-pyrimidine;Formate 348.4058

* ET 2-[2-(Biphenyl-3- ylmethylsulfanyl)-phenyl]- 1,4,5,6-tetrahydro-pyrimidine; HBr 439.4192

** EU 2-[2-(Naphthalen-2- yloxy)-phenyl]-1,4,5,6- tetrahydro-pyrimidine;Formate 348.4058

* EV 2-[2-(5-Bromo-2-methoxy- phenylmethanesulfinyl)-phenyl]-1,4,5,6-tetrahydro- pyrimidine 407.3311

* EW 2-[2-(5-Chloro-2-methoxy- benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro- pyrimidine; HCl 383.3404

*** EX 2-[2-(2-Methoxy-5- thiophen-3-yl-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro- pyrimidine; HCl 431.0216

*** EY 2-[2-(Biphenyl-2- ylmethylsulfanyl)-phenyl]- 1,4,5,6-tetrahydro-pyrimidine; Formate 404.5372

** EZ 2-[2-(5-Iodo-2-methoxy- benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro- pyrimidine; Formate 484.3622

*** FA 2-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-5-fluoro-phenyl]-1,4,5,6-tetrahydro- pyrimidine 409.3222

*** FB 2-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-3-fluoro-phenyl]-1,4,5,6- tetrahydro-pyrimidine 409.3222

*** FC 2-[2-(4,4′-Dimethoxy- biphenyl-3-ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro- pyrimidine; HBr 499.4717

** FD 2-[2-(9H-Fluoren-9- ylsulfanyl)-phenyl]- 1,4,5,6-tetrahydro-pyrimidine; HBr 437.4033

** FE 2-[2-(3′-Chloro-4′-fluoro-4- methoxy-biphenyl-3-ylmethylsulfanyl)-phenyl]- 1,4,5,6-tetrahydro- pyrimidine; Formate486.9987

** FF 2-[2-(1-Naphthalen-1-yl- ethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro- pyrimidine; HCl 382.9562

*** FG 2-[2-(4-Methoxy-biphenyl- 3-ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro- pyrimidine; Formate 434.5634

*** FH 2-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-5-fluoro-phenyl]-4,5-dihydro-1H- imidazole; Formate 441.3253

*** FI 2-(2-Benzhydrylsulfanyl- phenyl)-1,4,5,6-tetrahydro- pyrimidine;Formate 404.5372

*** FJ 2-(3-Amino-propylamino)- 6-(5-bromo-2-methoxy- benzylsulfanyl)-benzonitrile; Formate 452.3764

* FK 2-[2-(2′-Fluoro-4′- methoxy[1,1′,4′,1″]terphenyl-3″-ylmethylsulfanyl)-phenyl]- 1,4,5,6-tetrahydro- pyrimidine; formate528.6517

** FL 2-[2-(2-Methoxy-5- phenylethynyl-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro- pyrimidine; Formate 458.5854

** FM 2-[3-(Naphthalen-1- ylmethylsulfanyl)-phenyl]- 1,4,5,6-tetrahydro-pyrimidine; Formate 378.4993

* FN 4-Methoxy-N-[4-methyl-2- (1,4,5,6-tetrahydro-pyrimidin-2-yl)-phenyl]- benzamide; Formate 369.4248

* FO 2-(5-Bromo-2-methoxy- benzylsulfanyl)-benzamidine; formate 397.297

** FP 4,6-Dimethyl-2-piperazin- 1-yl-pyrimidine 192.264

* FQ 8-Isopropyl-3,3-dimethyl- 6-piperazin-1-yl-3,4-dihydro-1H-pyrano[3,4- c]pyridine-5-carbonitrile 314.4308

* FR 2-Piperazin-1-yl-pyrimidine 164.2102

* FS 1-Pyridin-2-yl-piperazine 163.2224

* FT 2-Piperazin-1-yl-4- trifluoromethyl-pyrimidine 232.2085

* FU 5-Piperazin-1-yl-7- trifluoromethyl-thieno[3,2-b]pyridine-3-carboxylic acid methyl ester 345.3454

* FV 5-Bromo-2-piperazin-1-yl- pyrimidine 243.1063

* FW 1-(3-Trifluoromethyl- pyridin-2-yl)-piperazine 231.2207

* FX 1-(5-Trifluoromethyl- pyridin-2-yl)-piperazine 231.2207

* FY Benzyl-[2-(1,4,5,6- tetrahydro-pyrimidin-2-yl)- phenyl]-amine265.3581

* FZ 2-[4-(Naphthalen-1- ylmethylsulfanyl)-phenyl]- 1,4,5,6-tetrahydro-pyrimidine; Formate 378.4993

** GA 2-[2-(5-Ethynyl-2- methoxy-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro- pyrimidine; HCl 372.9177

*** GB 2-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-benzyl]-1,4,5,6-tetrahydro- pyrimidine; HCl 441.8186

** GC 2-[2-(5-tert-Butyl-2- methoxy-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro- pyrimidine; HCl 405.0032

* GD 2-[2-(5-Bromo-2- cyclopentyloxy-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro- pyrimidine; Formate 491.4534

*** GE 2-[2-(5-Bromo-2-ethoxy- benzylsulfanyl-phenyl]-1,4,5,6-tetrahydro- pyrimidine; HCl 441.8186

*** GF 2-[2-(5-Bromo-2-propoxy- benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro- pyrimidine; HCl 455.8455

*** GG [2-(5-Bromo-2-methoxy- benzylsulfanyl)-benzyl]- diethyl-amine;HCl 430.8357

** GH 4-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-benzyl]- morpholine; HCl444.8192

* GI 1-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-benzyl]- piperazine;Oxalate 497.4145

** GK {1-[2-(5-Bromo-2- methoxy-benzylsulfanyl)-benzyl]-pyrrolidin-3-yl}- carbamic acid tert-butyl ester 507.4918

* GL 3′-(5-Bromo-2-methoxy- benzylsulfanyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl 395.3232

* GM C-{4-[3-(5-Bromo-2- methoxy-benzylsulfanyl)-quinoxalin-2-yl]-morpholin- 2-yl}-methylamine; 2HCl 548.3308

** GN 2-(5-Bromo-2-methoxy- benzylsulfanyl)-3-piperazin-1-yl-quinoxaline; Formate 491.4131

* GO 2-[2-(2-Methoxy-5-methyl- benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro- pyrimidine; HCl 362.9226

*** GP 2-[2-(5-Bromo-2-methoxy- benzyloxymethyl)-phenyl]-1,4,5,6-tetrahydro- pyrimidine; HCl 425.752

*** GQ 2-{2-[5-(3,3-Dimethyl-but- 1-ynyl)-2-methoxy-benzylsulfanyl]-phenyl}- 1,4,5,6-tetrahydro- pyrimidine; HCl 429.0252

* GR 3-Benzylidene-2-(2- methylamino-ethyl)-2,3- dihydro-isoindol-1-one278.3538

* GS 2-[2-(2-Naphthalen-1-yl- ethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine 346.4962

* GU [2-(5-Bromo-2-methoxy- benzylsulfanyl)-benzyl]- dimethyl-amine; HCl402.7819

** GV 2-[2-(5-Bromo-2- isopropoxy-benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro- pyrimidine; HCl 455.8455

*** GW 2-[2-(2-Ethoxy- naphthalen-1-ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro- pyrimidine; HCl 412.9824

*** GX 2-[2-(2-Propoxy- naphthalen-1-ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro- pyrimidine; HCl 427.0093

*** GY 4-Methoxy-3-[2-(1,4,5,6- tetrahydro-pyrimidin-2-yl)-phenylsulfanylmethyl]- benzonitrile; HCl 373.9055

*** GZ 1-(4-Methoxy-3-[2- (1,4,5,6-tetrahydro- pyrimidin-2-yl)-phenylsulfanylmethyl]- phenyl)-ethanone; Formate 400.503

** HA {1-[2-(2-Methoxy- naphthalen-1- ylmethylsulfanyl)-benzyl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester 478.6556

* HB 2-[2-(Naphthalen-1- ylsulfanylmethyl)-phenyl]- 1,4,5,6-tetrahydro-pyrimidine; HCl 368.9293

*** HC 2-(2-Phenethyl-phenyl)- 1,4,5,6-tetrahydro- pyrimidine; Formate310.4003

* HD 1-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-benzyl]- piperidine;Formate 452.4167

** HE {4-[2-(2-Methoxy- naphthalen-1- ylmethylsulfanyl)-benzyl]-morpholin-2-ylmethyl}- carbamic acid tert-butyl ester 508.6819

* HF C-{4-[2-(2-Methoxy- naphthalen-1-ylmethylsulfanyl)-benzyl]-morpholin-2-yl}- methylamine; 2HCl 481.486

** HG 1-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-benzyl]-pyrrolidin-3-ylamine; 2HCl 480.2959

** HH 2-[2-(Naphthalen-1- ylmethylsulfanyl)-phenyl]- 1H-imidazole316.4265

* HI 2-[2-(1-Benzyl-1H- imidazol-2- ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine 362.4986

* HJ 1-[3-(5-Bromo-2-methoxy- benzylsulfanyl)-pyrazin-2-yl]-pyrrolidin-3-ylamine; 2HCl 468.2446

* HK 1-[3-(5-Bromo-2-methoxy- benzylsulfanyl)-quinoxalin-2-yl]-pyrrolidin-3-ylamine; 2HCl 518.3045

* HL 1-[2-(2-Methoxy- naphthalen-1- ylmethylsulfanyl)-benzyl]-pyrrolidin-3-ylamine; HCl 414.9983

** HM 1-(5-Bromo-2-methoxy- benzyl)-2-phenyl-piperidine 360.2938

* HN 9-Benzyl-2,3,9,10- tetrahydro-1H-4,9,10a- triaza-phenanthrene;Formate 323.3991

* HO 2-[2-(2-Naphthalen-1-yl- ethyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine; Formate 360.4602

*** HP 3-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-3-fluoro-phenyl]-1,5,6,7,8,8a- hexahydro-imidazo[1,5- a]pyridine; HCl 485.847

*** HQ 3-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-3-fluoro-phenyl]-5,6,7,7a-tetrahydro- 1H-pyrrolo[1,2-c]imidazole; Formate481.3901

*** HR 2-[-2-(Benzo[b]thiophen-3- ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro- pyrimidine; HBr 419.4094

*** HS 2-[3-Fluoro-2-(naphthalen-1- ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro- pyrimidine; Formate 396.4897

*** HT 2-(Naphthalen-1- ylmethylsulfanyl)-3-(1,4,5,6-tetrahydro-pyrimidin-2-yl)- phenylamine; Formate 393.514

** HU 2-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-3-chloro-phenyl]-1,4,5,6-tetrahydro- pyrimidine 471.8065

*** HV C-{4-[3-(5-Bromo-2- methoxy-benzylsulfanyl)-pyrazin-2-yl]-morpholin-2- yl}-methylamine; Formate 471.3795

* HW Benzyl-methyl-[2-(1,4,5,6- tetrahydro-pyrimidin-2-yl)-phenyl]-amine; Formate 325.415

* HX 2-[2-(2-Methoxy- phenylsulfanylmethyl)- phenyl]-1,4,5,6-tetrahydro-pyrimidine; HCl 348.8957

** HY 1-{2-[2-(5-Bromo-2- methoxy-benzylsulfanyl)-phenyl]-5,6-dihydro-4H- pyrimidin-1-yl}-3-methyl- butan-1-one 475.4497

** HZ 2-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-phenyl]-5,6-dihydro-4H-pyrimidine-1- carboxylic acid benzyl 525.4662

** IA 1-{2-[2-(5-Bromo-2- methoxy-benzylsulfanyl)-phenyl]-5,6-dihydro-4H- pyrimidin-1-yl}-2-phenyl- ethanone 509.4668

*** IB 2-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-phenyl]-1-methanesulfonyl-1,4,5,6- tetrahydro-pyrimidine 469.4234

* IC 2-(5-Bromo-2-methoxy- benzylsulfanyl)-phenylamine 324.2413

* ID 2-o-Tolyl-1,4,5,6- tetrahydro-pyrimidine 174.2456

* IE 2-[3-(5-Bromo-2-methoxy- benzylsulfanyl)-pyridin-2-yl]-1,4,5,6-tetrahydro- pyrimidine 392.3195

*** IF 5-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-phenyl]-[1,3,4]oxadiazol-2-ylamine 392.2762

* IJ 2-(5-Bromo-2-methoxy- benzylsulfanyl)-benzoic acid hydrazide367.2664

* IK N-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-phenyl]- guanidine366.2817

** IL 2-[2-(2-Isopropoxy- naphthalen-1- ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro- pyrimidine; Formate 436.5793

** IM 2-[2-(2-Cyclopentyloxy- naphthalen-1- ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro- pyrimidine; HCl 453.0472

** IN (5-Bromo-2-methoxy- benzyl)-[2-(1,4,5,6-tetrahydro-pyrimidin-2-yl)- phenyl]-amine 374.2804

** IO 2-[2-(5-Bromo-2-methoxy- benzylsulfanylmethyl)-phenyl]-1,4,5,6-tetrahydro- pyrimidine; Formate 451.3886

*** IP 2-[2-(2-Methoxy- naphthalen-1- ylsulfanylmethyl)-phenyl]-1,4,5,6-tetrahydro- pyrimidine; HCl 398.9556

*** IQ 2-[3-(5-Bromo-2-methoxy- benzylsulfanyl)-pyrazin-2-yl]-1,4,5,6-tetrahydro- pyrimidine 393.3073

** IR 2-[3-Chloro-2- (naphthalen-1-ylsulfanylmethyl)-phenyl]-1,4,5,6-tetrahydro- pyrimidine; HCl 403.374

*** IS 2-[2-(6-Bromo-2-methoxy- naphthalen-1-ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro- pyrimidine; HCl 477.8516

*** IT 9-(5-Bromo-2-methoxy- benzyl)-2,3,9,10-tetrahydro-1H-4,9,10a-triaza-phenanthrene; Formate 432.3214

* IU 2-[3-Chloro-2-(2-methoxy- naphthalen-1-ylsulfanylmethyl)-phenyl]-1,4,5,6-tetrahydro- pyrimidine 396.9403

*** IV 2-[2-(2,7-Dimethoxy- naphthalen-1- ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro- pyrimidine; Formate 438.5518

* IW 2-Piperazin-1-yl-pyridine- 3-sulfonic acid ethylamide 270.3557

* IX 7-Methoxy-3-(4-nitro- phenyl)-2-piperazin-1-yl- quinoline 364.404

* IY 4-Methyl-2-piperazin-1-yl- quinoline 227.3092

* IZ 2-[2-(5-Bromo-2-methoxy- phenylsulfanylmethyl)-phenyl]-1,4,5,6-tetrahydro- pyrimidine; HCl 427.7917

*** JA 2-[2-(5-Bromo-2-methoxy- phenylsulfanylmethyl)-3-chloro-phenyl]-1,4,5,6- tetrahydro-pyrimidine; HCl 462.2365

*** JB 3-(5-Bromo-2-methoxy- benzylsulfanyl)-2-(1,4,5,6-tetrahydro-pyrimidin-2-yl)- quinoline 442.3794

* JC 2-[1-(2-Naphthalen-1-yl- ethyl)-1H-pyrrol-2-yl]-1,4,5,6-tetrahydro-pyrimidine 303.407

** JD (5-Bromo-2-methoxy- benzyl)-methyl-[2-(1,4,5,6-tetrahydro-pyrimidin-2-yl)- phenyl]-amine 388.3073

** JE [2-(5-Bromo-2-methoxy- benzylsulfanyl)-phenyl]- methyl-amine338.2682

* JF 2-(5-Bromo-2-methoxy- benzylsulfanyl)-benzylamine; HCl 374.7282

** JK 2-[2-(2-Chloro- phenylsulfanylmethyl)- phenyl]-1,4,5,6-tetrahydro-pyrimidine; HCl 353.3142

** JL 2-[2-(2-Bromo- phenylsulfanylmethyl)- phenyl]-1,4,5,6-tetrahydro-pyrimidine; HCl 397.7655

** JM 2-(2-o- Tolylsulfanylmethyl- phenyl)-1,4,5,6-tetrahydro-pyrimidine; HCl 332.8963

** JN 2-[2-(2,5-Dichloro- phenylsulfanylmethyl)-phenyl]-1,4,5,6-tetrahydro- pyrimidine; HCl 387.7589

*** JO 2-[3-(3-Chloro- benzylsulfanyl)-5-methyl-isothiazol-4-yl]-1,4,5,6- tetrahydro-pyrimidine; Formate 383.927

* JP N-(4-Methyl-quinazolin-2- yl)-guanidine; HCl 237.691

* JQ N-(1-Methyl-benzo[f]- quinazolin-3-yl)-guanidine; HCl 287.7509

* JR 2-[3-(2-Methoxy- naphthalen-1-ylsulfanylmethyl)-thiophen-2-yl]-1,4,5,6- tetrahydro-pyrimidine; Formate 414.5537

** JS 2-[2-(2,5-Dimethoxy- phenylsulfanylmethyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine 342.462

** JT 2-[2-(4-Methyl- naphthalen-1-ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro- pyrimidine; HCl 382.9562

*** JU 2-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-3-fluoro-phenyl]-4,4-dimethyl-4,5- dihydro-1H-imidazole; HCl 459.8091

*** JV 2-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-3-fluoro-phenyl]-5,5-dimethyl- 1,4,5,6-tetrahydro- pyrimidine; HCl 473.836

*** JW Methyl-naphthalen-1-yl- [2-(1,4,5,6-tetrahydro-pyrimidin-2-yl)-benzyl]- amine; Formate 375.4748

* JX Methyl-[2-(1,4,5,6- tetrahydro-pyrimidin-2-yl)- phenyl]-amine189.2603

* JY 2-(5-Bromo-2-methoxy- benzylsulfanyl)-3-(1,4,5,6-tetrahydro-pyrimidin-2-yl)- quinoxaline 443.3672

* JZ 2-[3-(Naphthalen-1- ylsulfanylmethyl)-thiophen-2-yl]-1,4,5,6-tetrahydro- pyrimidine; Formate 384.5274

*** KA 2-[6-(2-Naphthalen-1-yl- ethoxy)-pyridin-2-yl]-1,4,5,6-tetrahydro- pyrimidine; Formate 377.4474

* KB 2-{2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]- phenyl}-1,4,5,6-tetrahydro-pyrimidine 373.2926

*** KC 10-(5-Bromo-2-methoxy- phenyl)-9-methyl- 2,3,9,10-tetrahydro-1H-4,9,10a-triaza- phenanthrene; Formate 432.3214

* KD 2-Morpholin-4-ylmethyl- quinazolin-4-ol 245.2811

* KE N,N-Dimethyl-N′-(4- phenyl-quinazolin-2-yl)- ethane-1,2-diamine292.3838

* KF 4-Phenyl-2-piperazin-1-yl- quinazoline 290.3679

* KG 2-[3-Chloro-2-(2- naphthalen-1-yl-ethyl)-phenyl]-1,4,5,6-tetrahydro- pyrimidine; HCl 385.3349

*** KH 2-{2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-3-fluoro-phenyl)-1,4,5,6- tetrahydro-pyrimidine; HCl 427.7431

*** KI 1-(2-Naphthalen-1-yl- ethyl)-6-(1,4,5,6-tetrahydro-pyrimidin-2-yl)-1H-pyridin- 2-one; Formate 377.4474

* KJ 2-[2-(5-Bromo-2-methoxy- phenylsulfanylmethyl)-3-fluoro-phenyl]-1,4,5,6- tetrahydro-pyrimidine; HCl 445.7822

*** KK 2-[2-(Naphthalen-1- ylsulfanylmethyl)-phenyl]-4,5-dihydro-1H-imidazole; HCl 354.9024

*** KL 2-[3-Fluoro-2- (naphthalen-1-ylsulfanylmethyl)-phenyl]-1,4,5,6-tetrahydro- pyrimidine; HCl 386.9197

*** KM 2-[3-Bromo-2- (naphthalen-1-ylsulfanylmethyl)-phenyl-1,4,5,6-tetrahydro- pyrimidine; HCl 447.8253

*** KN 2-{2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-3-chloro-phenyl}-1,4,5,6- tetrahydro-pyrimidine; HCl 444.1974

*** KO 6-Benzylsulfanyl-5- (1,4,5,6-tetrahydro-pyrimidin-2-yl)-imidazo[2,1-b]thiazole; Formate 374.492

* KP 2-[3-(5-Bromo-2-methoxy- phenylsulfanyl)propyl]-1,4,5,6-tetrahydro-pyrimidine; Formate 389.3177

* KQ 2-[2-(2-Methoxy-5- trifluoromethyl- benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro-pyrimidine 380.4339

*** KR 9-Methyl-10-naphthalen- 1-yl-2,3,9,10-tetrahydro-1H-4,9,10a-triaza-phenanthrene; Formate 373.459

* KS 7-Chloro-4,8-dimethyl-1H- quinolin-2-one 207.6592

* KT 7-Chloro-4-methyl-2- piperazin-1-yl-quinoline 261.754

* KU 4,8-Dimethyl-2-piperazin- 1-yl-quinoline 241.3361

* KV 2-[4-(Naphthalen-1- ylsulfanylmethyl)- thiophen-3-yl]-1,4,5,6-tetrahydro-pyrimidine; HCl 374.9574

** KW 2-[2-(Naphthalen-1- ylsulfanylmethyl)-thiophen-3-yl]-1,4,5,6-tetrahydro- pyrimidine; HCl 374.9574

*** KX 6-(2-Methoxy-phenyl)-3,4- dihydro-2H-pyrimido[2,1-a]isoquinoline; Formate 336.3948

* KY Piperazine 86.1369

* KZ 2-[2-(4-Fluoro- naphthalen-1-ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro- pyrimidine; HBr 431.3717

*** LA 7-Ethyl-4-methyl-2- piperazin-1-yl-quinoline 255.363

* LB 6-Ethyl-4-methyl-2- piperazin-1-yl-quinoline 255.363

* LC 5,8-Dimethoxy-4-methyl- 2-piperazin-1-yl-quinoline 287.3618

* LD 2-{2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-3-trifluoromethyl-phenyl}- 1,4,5,6-tetrahydro- pyrimidine; Parent 441.2909

*** LE 2-[2-(2-Naphthalen-1-yl- ethyl)-3-trifluoromethyl-phenyl]-1,4,5,6-tetrahydro- pyrimidine; HCl 418.8884

*** LF 2-[4-Benzyloxy-2-(5- bromo-2-methoxy- benzylsulfanyl)-phenyl]-1,4,5,6-tetrahydro- pyrimidine; Formate 543.4858

** LG [3-(5-Bromo-2-methoxy- benzylsulfanyl)-quinoxalin-2-yl]-(3-pyrrolidin-1-yl- propyl)-amine; formate 533.4937

* LH Naphthalen-1-ylmethyl-[2- (1,4,5,6-tetrahydro-pyrimidin-2-yl)-phenyl]-amine; Formate 361.448

* LI [3-(5-Bromo-2-methoxy- benzylsulfanyl)-quinoxalin-2-yl]-[2-(1-methyl-pyrrolidin- 2-yl)-ethyl]-amine; Formate 533.4937

* LJ [3-(5-Bromo-2-methoxy- benzylsulfanyl)-quinoxalin-2-yl)-[3-(2-methyl-piperidin-yl)- propyl]-amine; Formate 561.5475

* LK [3-(5-Bromo-2-methoxy- benzylsulfanyl)- quinoxalin-2-yl]-piperidin-4-ylmethyl-amine; Formate 519.4669

* LM 2-[1,4′]Bipiperidinyl-1′-yl- 3-(5-bromo-2-methoxy- benzylsulfanyl)-quinoxaline; Formate 573.5585

* LN N1-[3-(5-Bromo-2- methoxy-benzylsulfanyl)-quinoxalin-2-yl]-propane- 1,3-diamine; 2HCl 506.2935

* LO 2-[1,4′]Bipiperidinyl-1′-yl- 3-(5-bromo-2-methoxy- benzylsulfanyl)-quinoxaline; Formate 581.5377

* LP 2-(5-Bromo-2-methoxy- benzylsulfanyl)-3-[4-(3-morpholin-4-yl-propyl)- piperazin-1-yl]- quinoxaline; Formate 618.5995

* LQ 4-[2-(5-Bromo-2-methoxy- benzylsulfanyl)- benzylamino]-piperidine-1-carboxylic acid ethyl ester; Formate 539.4949

* LR 1-[2-(Naphthalen-1- ylmethylsulfanyl)-benzyl]- piperidine 347.5242

* LS 2-{4-[2-(5-Bromo-2- methoxy-benzylsulfanyl)-benzyl]-piperazin-1-yl]- pyrimidine; Formate 531.4779

* LT 2-[2-(6-Fluoro-naphthalen- 1-ylmethylsulfanyl)-phenyl]-1,4,5,6-tetrahydro- pyrimidine; HBr 431.3717

*** LU 1-{4-[2-(5-Bromo-2- methoxy-benzylsulfanyl)-benzyl]-piperazin-1-yl)- ethanone; Formate 495.4418

* LV 2-(2-{4-[2-(5-Bromo-2- methoxy-benzylsulfanyl)-benzyl]-piperazin-1-yl)- ethoxy)-ethanol; Formate 541.5108

* LW 2-{4-[2-(5-Bromo-2- methoxy-benzylsulfanyl)-benzyl]-piperazin-1-yl}-N- isopropyl-acetamide; Formate 552.5371

** LX {1-[2-(5-Bromo-2- methoxy-benzylsulfanyl)-benzyl]-piperidin-2-yl}- methanol; Formate 482.443

*** LY 1-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-benzyl]-2-(N-pyrrolo)methyl- pyrrolidine; Formate 521.523

* LZ 1′-[2-(5-Bromo-2- methoxy-benzylsulfanyl)-benzyl]-[1,4′]bipiperidinyl; Formate 535.5499

* MA 1-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-benzyl]-4-cycloheptyl-piperazine; Formate 549.5768

* MB 3-{2-[2-(1,4,5,6- Tetrahydro-pyrimidin-2- yl)-phenyl]-ethyl}-1H-indole 349.437

* MC N′-[3-(5-Bromo-2- methoxy-benzylsulfanyl)- quinoxalin-2-yl]-N,N-diethyl-ethane-1,2- diamine; Formate 521.4827

* MD N′-[3-(5-Bromo-2- methoxy-benzylsulfanyl)- quinoxalin-2-yl]-N,N-dimethyl-propane-1,3- diamine; Formate 507.4559

* ME 2-(5-Bromo-2-methoxy- benzylsulfanyl)-3- [1,4]diazepan-1-yl-quinoxaline; Formate 505.44

* MF N-(4-Bromo-benzyl)-N′,N′- dimethyl-N-naphthalen-1-ylmethyl-ethane-1,2- diamine 397.358

* MG 3′-(5-Bromo-2-methoxy- benzylsulfanyl)-4-(3-morpholin-4-yl-propyl)- 3,4,5,6-tetrahydro-2H- [1,2′]bipyrazinyl;Formate 568.5396

* MH {3-[3′-(5-Bromo-2- methoxy-benzylsulfanyl)- 2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl]- propyl}-dimethyl-amine; Formate 526.5023

* MI N-(3-Bromo-benzyl)-N-(5- bromo-2-methoxy-benzyl-N′,N′-dimethyl-ethane-1,2- diamine 456.2204

* MJ N-(1-Benzyl-piperidin-4- yl)-2-(naphthalen-1-ylmethylsulfanyl)-benzamide 466.6471

* MK N,N-Dimethyl-N′- naphthalen-2-ylmethyl-N′- naphthalen-1-ylmethyl-ethane-1,2-diamine 368.5218

* ML 8-Methyl-3-[2- (naphthalen-1- ylsulfanylmethyl)-phenyl]-8-aza-bicyclo[3.2.1]octan- 3-ol; Formate 435.5915

** MM 1-Methyl-4-[2- (naphthalen-1- ylsulfanylmethyl)-phenyl]-piperidin-4-ol; Formate 409.5536

* MN 3-[2-(Naphthalen-1- ylsulfanylmethyl)-phenyl]-1-aza-bicyclo[2.2.2]octan- 3-ol; Formate 421.5646

* MO 1′-[3-(5-Bromo-2- methoxy-benzylsulfanyl)- pyrazin-2-yl]-[1,4′]bipiperidinyl 477.4686

* MP [3-(5-Bromo-2-methoxy- benzylsulfanyl)-pyrazin-2-yl]-[2-(1-methyl-pyrrolidin- 2-yl)-ethyl]-amine 437.4039

* MQ [3-(5-Bromo-2-methoxy- benzylsulfanyl)-pyrazin-2-yl]-[3-(2-methyl-piperidin- 1-yl)-propyl]-amine 465.4576

* MR N-(3-Chloro-benzyl)-N-(2- methoxy-benzyl)-N′,N′-dimethyl-ethane-1,2-diamine 332.8731

* MS N-(3-Bromo-benzyl)-N′,N′- dimethyl-N-(4-methyl-benzyl)-ethane-1,2-diamine 381.7429

* MT N-(3-Bromo-benzyl)-N′,N′- dimethyl-N-naphthalen-2-ylmethyl-ethane-1,2-diamine 397.358

* MU N-(3-Bromo-benzyl)-N′,N′- dimethyl-N-(4-methyl-benzyl)-ethane-1,2-diamine 361.325

* MV N-Benzyl-N-(2-methoxy- benzyl)-N′,N′-dimethyl- ethane-1,2-diamine298.4283

* MW N-Benzyl-N-(2-chloro- benzyl)-N′,N′-dimethyl- ethane-1,2-diamine302.8468

* MX N-Benzyl-N′,N′-dimethyl- N-naphthalen-1-ylmethyl-ethane-1,2-diamine 318.4619

* MY N-(5-Bromo-2-methoxy- benzyl)-N′,N′-dimethyl-N-naphthalen-1-ylmethyl- ethane-1,2-diamine 427.3843

* MZ 8-Methyl-3-[2-(naphthalen- 1-ylsulfanylmethyl)-phenyl]-8-aza-bicyclo[3.2.1]oct-2-ene 371.5462

** NA 1-Ethyl-3-[2-(naphthalen- 1-ylsulfanylmethyl)-phenyl]-piperidin-3-ol; Formate 423.5805

* NB 1-Methyl-4-[2-(naphthalen- 1-ylsulfanylmethyl)-phenyl]-1,2,3,6-tetrahydro-pyridine; Formate 391.5384

** NC 2-Phenyl- cyclopropanecarboxylic- acid 2-dimethylamino-ethyl)-naphthalen-1-ylmethyl-amide 372.5102

* ND N-Anthracen-9-ylmethyl- N′,N′-dimethyl-N- naphthalen-1-ylmethyl-ethane-1,2-diamine 418.5817

* NE N,N-Dimethyl-N′,N′-bis- naphthalen-1-ylmethyl- ethane-1,2-diamine368.5218

* NF N-(2-Methoxy-naphthalen- 1-ylmethyl)-N′,N′-dimethyl-N-naphthalen-1-ylmethyl- ethane-1,2-diamine 398.5481

* NG 1-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-3-chloro-benzyl]-piperidine 440.8315

* NH 2-[3-Fluoro-2-(2- naphthalen-1-yl-ethyl)-phenyl]-1,4,5,6-tetrahydro- pyrimidine; HCl 368.8806

*** NI 3-(3,4-Dichloro-phenyl)-1- (2-dimethylamino-ethyl)-1-naphthalen-1-ylmethyl-urea 416.3496

* NJ 3-(3,5-Dichloro-phenyl)-1- (2-dimethylamino-ethyl)-1-naphthalen-1-ylmethyl-urea 416.3496

* NK 1-(2-Dimethylamino-ethyl)- 1-naphthalen-1-ylmethyl-3-(2-trifluoromethyl-phenyl)-urea 415.4584

* NL 1-(2-Dimethylamino- ethyl)-3-(4-methoxy- phenyl)-1-naphthalen-1-ylmethyl-urea 377.4864

* NM 1-(2-Dimethylamino- ethyl)-1-naphthalen-1-ylmethyl-3-phenethyl-urea 375.5139

* NN 1-(2-Dimethylamino- ethyl)-1-naphthalen-1- ylmethyl-3-propyl-urea313.443

* NO 1-(2-Dimethylamino- ethyl)-3-(4-methoxy-benzyl)-1-naphthalen-1-ylmethyl-urea 391.5133

* NP 3-(3-Cyano-phenyl)-1-(2- dimethylamino-ethyl)-1-naphthalen-1-ylmethyl-urea 372.4699

* NQ 3-(2,6-Dichloro-pyridin-4- yl)-1-(2-dimethylamino-ethyl)-1-naphthalen-1- ylmethyl-urea 417.3374

* NR [2-(Naphthalen-2- ylmethylsulfanyl)-phenyl]- carbamic acid2-piperidin- 1-yl-ethyl ester; formate 466.6056

* NS [2-(Naphthalen-2- ylmethylsulfanyl)-phenyl]- carbamic acid 1-aza-bicyclo[2.2.2]oct-3-yl- ester; formate 464.5897

* NT [2-(5-Bromo-2-methoxy- benzylsulfanyl)-phenyl]- carbamic acid2-piperidin- 1-yl-ethyl ester 525.4681

** NU [2-(5-Bromo-2-methoxy- benzylsulfanyl)-phenyl]- carbamic acid1-aza- bicyclo[2.2.2]oct-3-yl- ester; formate 523.4522

* NV [2-(5-Bromo-2-methoxy- benzylsulfanyl)-3-chloro-benzyl]-[3-(2-methyl- piperidin-1-yl)-propyl]- amine; 2HCl 584.8751

*** NW 1-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-3-chloro-benzyl]-piperazine; 2HCl 514.7407

*** NX 1-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-3-chloro-benzyl]-pyrrolidin-3-ol; Formate 488.834

* NY {1-[2-(5-Bromo-2- methoxy-benzylsulfanyl)-3-chloro-benzyl]-pyrrolidin- 2-yl}-methanol; Formate 502.8609

* NZ 1-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-3-chloro-benzyl]-azetidine; Formate 458.8077

* OA 1-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-3-chloro-benzyl]-pyrrolidin-3-ol; Formate 488.834

* OB [2-(Naphthalen-1- ylmethylsulfanyl)-phenyl]- carbamic acid1-aza-bicyclo [2.2.2]oct-3-yl ester; Formate 464.5897

* OC [2-(2-Methyl-naphthalen- 1-ylmethylsulfanyl)-phenyl]- carbamic acid1-aza-bicyclo [2.2.2]oct-3-yl ester; Formate 478.6166

** OD [2-(2-Methyl-naphthalen- 1-ylmethylsulfanyl)-phenyl]- carbamicacid 2-piperidin-1- yl-ethyl ester; Formate 480.6325

* OE {1-[2-(5-Bromo-2- methoxy-benzylsulfanyl)-3-chloro-benzyl]-pyrrolidin-2- yl]-methanol; Formate 502.8609

* OF Naphthalen-2-ylmethyl- naphthalen-1-ylmethyl-(2-piperidin-1-yl-ethyl)-amine 408.5866

* OG 4-tert-Butyl-N-naphthalen- 1-ylmethyl-N-(2-piperidin-1-yl-ethyl)-benzamide 428.6177

* OH N,N-Dimethyl-N′- naphthalen-2-ylmethyl-N′- naphthalen-1-ylmethyl-propane-1,3-diamine 382.5487

* OI N-(5-Bromo-2-methoxy- benzyl)-N′,N′-dimethyl-N-naphthalen-1-ylmethyl- propane-1,3-diamine 441.4111

* OJ 1-Naphthalen-1-ylmethyl- 3-phenethyl-1-(2- piperidin-1-yl-ethyl)-thiourea; HCl 468.1052

* OK 3-(4-Dimethylamino-phenyl)- 1-(3-dimethylamino-propyl)-1-naphthalen-1-ylmethyl- thiourea; HCl 457.082

*** OL 4-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-3-chloro-benzylamino]-piperidine- 1-carboxylic acid ethyl ester; Formate 573.9397

** OM 1-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-3-chloro-benzyl]-pyrrolidin-3- ylamine; 2HCl 514.7407

*** ON 2-[2-(2-Naphthalen-1-yl- ethyl)-phenyl]- ethylamine; HCl 311.8535

** OO Naphthalene-2-sulfonic- acid (2-dimethylamino-ethyl)-naphthalen-1- ylmethyl-amide 418.5597

* OP 1-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-3-chloro-benzyl]-2-methoxymethyl- pyrrolidine; Formate 516.8877

* OQ (2-Hexyloxy-phenyl)- carbamic acid 2-piperidin- 1-yl-1-piperidin-1-ylmethyl-ethyl ester; Formate 491.6758

** OR 3-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-benzyloxy]- pyrrolidine;HCl 444.8192

** OS 3-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-benzyloxy]- pyrrolidine;HCl 444.8192

** OT 2-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-benzyloxy-methyl]-pyrrolidine; HCl 458.8461

** OU 2-[2-(Naphthalen-1- ylsulfanylmethyl)-phenyl]- piperidine; HCl369.9574

* OV 3-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-benzylamino]- propan-1-ol396.3482

* OW 3-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-benzylamino]-3-methyl-butan-1-ol 424.402

** OX 1-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-benzyl]- pyrrolidin-3-ol408.3592

* OY 1-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-benzyl]- pyrrolidin-3-ol408.3592

* OZ {1-[2-(5-Bromo-2- methoxy-benzylsulfanyl)-benzyl]-pyrrolidin-2-yl}- methanol 422.3861

* PA {1-[2-(5-Bromo-2- methoxy-benzylsulfanyl)-benzyl]-pyrrolidin-2-yl}- methanol 422.3861

* PB {1-[2-(Naphthalen-1- ylsulfanylmethyl)-benzyl]-piperidin-2-yl}-methanol; Formate 423.5805

* PC 2-[2-(Naphthalen-1- ylsulfanylmethyl)- pyrrolidin-1-yl]-ethyl-N-pyrrolidine; Formate 386.5628

* PD N-pyrrolyl-[1-(2- naphthalen-1-yl-ethyl)- pyrrolidin-2-ylmethyl]-amine 308.4668

* PE 1-(2-Naphthalen-1-yl- ethyl)-piperidine-2- carboxylic acid methylester 297.3972

* PF (3-Bromo-benzyl)-(1- ethyl-pyrrolidin-2- ylmethyl)-naphthalen-1-ylmethyl-amine 437.4227

* PG 3-[2-(5-Bromo-2-methoxy- benzylsulfanyl)- benzyloxy]-piperidine;HCl 458.8461

** PH (5-Bromo-2-methoxy- benzyl)-(1-ethyl-pyrrolidin-2-ylmethyl)-naphthalen-1- ylmethyl-amine 467.449

* PI (1-Ethyl-pyrrolidin-2- ylmethyl)-naphthalen-2-ylmethyl-naphthalen-1- ylmethyl-amine 408.5866

* PJ 2-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-benzyloxy-methyl]-pyrrolidine; HCl 458.8461

** PK (3-Bromo-benzyl)-(3- imidazol-1-yl-propyl)- naphthalen-1-ylmethylamine 434.3788

* PL (3-Imidazol-1-yl-propyl)- naphthalen-2-ylmethyl-naphthalen-1-ylmethyl-amine 405.5426

* PM [2-(Naphthalen 1- ylmethylsulfanyl)-phenyl]- carbamic acid2-piperidin- 1-yl-1-piperidin-1-ylmethyl- ethyl ester; Formate 563.7657

* PN [2-(Naphthalen-1- ylmethylsulfanyl-phenyl]- carbamic acid 2-dimethylamino-ethyl ester; Formate 426.5408

* PO 1-[2-(Naphthalen-1- ylsulfanylmethyl)-benzyl]- piperazine; Formate394.542

** PP [3-(2-Methyl-piperidin-1- yl)-propyl]-[2-(naphthalen-1-ylsulfanylmethyl)- benzyl]-amine; Formate 464.6764

** PQ 1-[3-Chloro-2- naphthalen-1- ylsulfanylmethyl)-benzyl]-piperazine; HCl 419.4168

** PR 1-[3-Fluoro-2-(2- naphthalen-1-yl-ethyl)- benzyl]-piperazine; HCl384.9234

*** PS {1-[3-Chloro-2- (naphthalen-1-ylsulfanyl-methyl)-benzyl]-piperidin- 2-yl}-methanol; Formate 458.0253

* PT N,N-Dimethyl-N′-(2- naphthalen-1-yl-ethyl)-N′-naphthalen-1-ylmethyl- ethane-1,2-diamine; Formate 428.5787

* PU {1-[2-(5-Bromo-2- methoxy-benzylsulfanyl)-3-chloro-benzyl]-piperidin- 2-yl)-methanol 470.8577

* PV {1-[2-(2-Naphthalen-1-yl- ethyl)-benzyl]-piperidin-2- yl)-methanol;Formate 405.5414

* PW 1-[2-(2-Naphthalen-1-yl- ethyl)-benzyl]-piperazine; Formate376.5029

* PX [3-(2-Methyl-piperidin-1- yl)-propyl]-[2-(2-naphthalen-1-yl-ethyl)- benzyl]-amine; Formate 446.6373

* PY 1-[2-(2-Naphthalen-1-yl- ethyl)-benzyl]-pyrrolidin-3- ylamine;Formate 376.5029

** PZ 5,5-Dimethyl-2-[2-(2- naphthalen-1-yl-ethyl)-phenyl]-4,5-dihydro-1H- imidazole

*** QA 2-[3-Fluoro-2-(2- naphthalen-1-yl-ethyl)-phenyl]-5,5-dimethyl-4,5- dihydro-1H-imidazole

*** QB 2-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-3,5-difluoro-phenyl]-1,4,5,6- tetrahydro-pyrimidine

*** QC 2-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-3,5-difluoro-phenyl]-5,5- dimethyl-4,5-dihydro-1H- imidazole

** QD 3-(2-Naphthalen-1-yl- ethyl)-2-(1,4,5,6-tetrahydro-pyrimidin-2-yl)- phenylamine

* QE Amino-[2-(2-naphthalen- 1-yl-ethyl)-phenyl]- acetonitrile

* QF 1-[2-(2-Naphthalen-1-yl- ethyl)-phenyl]-ethane-1,2- diamine

** QG 2-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-phenyl]-4-methyl-4,5-dihydro-1H- imidazole

** QH 2-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-3-fluoro-phenyl]-4-methyl-4,5- dihydro-1H-imidazole

*** QI 2-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-3-chloro-phenyl]-4-methyl-4,5- dihydro-1H-imidazole

*** OJ 2-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-3,4-difluoro-phenyl]-1,4,5,6- tetrahydro-pyrimidine

*** OK 2-[3-Fluoro-2- (naphthalen-1- ylsulfanylmethyl)-phenyl]-5,5-dimethyl-4,5-dihydro- 1H-imidazole

** QL 2-{2-[2-(5-Bromo-2- methoxy-phenyl)-1- methyl-ethyl]-phenyl)-1,4,5,6-tetrahydro- pyrimidine

*** QM 2-[2-(5-Bromo-2-methoxy- benzyl sulfanyl)-3-fluoro-4-trifluoromethyl-phenyl]-4,4- dimethyl-4,5-dihydro-1H- imidazole

* QN 2-[2-(5-Bromo-2-methoxy- benzyl sulfanyl)-3-fluoro-4-trifluoromethyl-phenyl]-5,5- dimethyl-1,4,5,6-tetrahydro- pyrimidine

* QO 2-[3-Methoxy-2-(2- naphthalen-1-yl-ethyl)- phenyl]-1,4,5,6-tetrahydro-pyrimidine

*** QP 2-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-3-chloro-phenyl]-1,4,5,6- tetrahydro-pyrimidin-5-ol

*** QQ 2-{2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-3-methoxy-phenyl}-1,4,5,6- tetrahydro-pyrimidine

*** QR 2-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-3-chloro-phenyl]-1,4,5,6- tetrahydro-pyrimidin-5-ol

*** QS 1-Amino-3-[2-(5-bromo-2- methoxy-phenyl)-7-chloro-benzo[b]thiophen-3- ylamino]-propan-2-ol

* OT 2-[2-(1-Methyl-2- naphthalen-1-yl-ethyl)- phenyl]-1,4,5,6-tetrahydro-pyrimidine

** QU 3-(5-Bromo-2-methoxy- benzylsulfanyl)-2-fluoro-4-(1,4,5,6-tetrahydro- pyrimidin-2-yl)- phenylamine

* QV 2-{2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-3-methyl-phenyl)-1,4,5,6- tetrahydro-pyrimidine

*** QW 2-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-3-fluoro-phenyl]-1,4,5,6- tetrahydro-pyrimidin-5-ol

*** QX 1-Amino-3-[2-(5-bromo-2- methoxy-phenyl)-7-fluoro-benzo[b]thiophen-3- ylamino]-propan-2-ol

* QY 2-[3-Methoxy-2- (naphthalen-1- ylsulfanylmethyl)-phenyl]-1,4,5,6-tetrahydro- pyrimidine

*** QZ 2-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-3-fluoro-phenyl]-1,4,5,6- tetrahydro-pyrimidin-5-ol

*** RA 2-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-5-methoxy-phenyl]-1,4,5,6- tetrahydro-pyrimidine

** RB 2-{2-[2-Chloro-6-(1,4,5,6- tetrahydro-pyrimidin-2-yl)-phenyl]-ethyl}-phenol

*** RC 2-[3-Methoxy-2- (naphthalen-1- ylsulfanylmethyl)-phenyl]-1,4,5,6-tetrahydro- pyrimidin-5-ol

*** RD 2-{2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-3-methyl-phenyl}-5-methyl- 4,5-dihydro-1H-imidazole

*** RE 2-{2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-3-methyl-phenyl}-1,4,5,6- tetrahydro-pyrimidin-5-ol

*** RF 2-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-3,4-difluoro-phenyl]-1,4,5,6- tetrahydro-pyrimidin-5-ol

** RG 2-{2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-3- chloro-phenyl}-4,4-dimethyl-4,5-dihydro-1H- imidazole

*** RH 2-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-3-fluoro-4-methyl-phenyl]-1,4,5,6- tetrahydro-pyrimidine

** RI 4,4-Dimethyl-2-[2- (naphthalen-1- ylmethylsulfanyl)-phenyl]-4,5-dihydro-oxazole

* RJ 2-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-4-methoxy-phenyl]-1,4,5,6- tetrahydro-pyrimidine

* RK 2-[5-(5-Bromo-2-methoxy- benzyl)-2-methyl- thiophen-3-yl]-1,4,5,6-tetrahydro-pyrimidine

** RL 2-{2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-thiophen-3-yl}-1,4,5,6- tetrahydro-pyrimidine

*** RM 2-{2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-3-ethoxy-phenyl)-1,4,5,6- tetrahydro-pyrimidine

*** RN 2-{2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-3- isopropoxy-phenyl}-1,4,5,6-tetrahydro- pyrimidine

*** RO 2-{2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-3-fluoro-4-methoxy-phenyl}- 1,4,5,6-tetrahydro- pyrimidine

* RP 2-{2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-3- isopropoxy-phenyl}-1,4,5,6-tetrahydro- pyrimidin-5-ol

** RQ 2-{2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-3-methoxy-phenyl}-1,4,5,6- tetrahydro-pyrimidin-5-ol

*** RS 2-{2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-4-methoxy-phenyl}-1,4,5,6- tetrahydro-pyrimidine

* RT 2-{2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-3-ethoxy-phenyl}-1,4,5,6- tetrahydro-pyrimidin-5-ol

*** RU 2-[2-(5-Bromo-2-methoxy- phenyl)-ethyl]-3-(1,4,5,6-tetrahydro-pyrimidin-2-yl)- benzonitrile

*** RV 2-{3-Benzyloxy-2-[2-(5- bromo-2-methoxy- phenyl)-ethyl]phenyl}-1,4,5,6-tetrahydro- pyrimidine

* RW 2-{2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-4-butyl-phenyl}-1,4,5,6- tetrahydro-pyrimidine

* RX 2-{5-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]- 2,3-dihydro-benzo[1,4]-dioxin-6-yl)-1,4,5,6- tetrahydro-pyrimidine

** RY 2-{5-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-8- chloro-2,3-dihydro-benzo[1,4]dioxin-6-yl}- 1,4,5,6-tetrahydro- pyrimidine

** RZ 2-{2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-3-ethyl-phenyl}-1,4,5,6- tetrahydro-pyrimidine

*** SA 2-{2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-3-propyl-phenyl}-1,4,5,6- tetrahydro-pyrimidine

*** SB 2-{2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-3-butoxy-phenyl)-1,4,5,6- tetrahydro-pyrimidine

** SC 2-{2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-3-isobutoxy-phenyl}-1,4,5,6- tetrahydro-pyrimidine

** SD 2-{2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-3-butoxy-phenyl)-1,4,5,6- tetrahydro-pyrimidin-5-ol

** SE 2-[2-(5-Bromo-2-methoxy- benzylsulfanyl-3-fluoro-phenyl]-5-methoxy- 1,4,5,6-tetrahydro- pyrimidine

*** SF 2-{2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-3-chloro-phenyl}-1-methyl- 1,4,5,6-tetrahydro- pyrimidine

*** SG 2-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-3-fluoro-phenyl]-1-methyl-4,5- dihydro-1H-imidazole

*** SH [2-(5-Bromo-2-methoxy- benzylsulfanyl)-3-fluoro-phenyl]-1-methyl-4,5- dihydro-1H-imidazole

*** SI 2-{2-[3-(1,4,5,6- Tetrahydro-pyrimidin-2-yl)-biphenyl-2-yl]-ethyl}- phenol

*** SJ 2-{2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-3-chloro-phenyl)-1-methyl- 4,5-dihydro-1H-imidazole

*** SK N-(3-Amino-propyl)-2-[2- (5-bromo-2-methoxy-phenyl)-ethyl]-6-methoxy- benzamide

* SL N-(3-Amino-propyl)-2-[2- (5-bromo-2-methoxy-phenyl)-ethyl]-6-methyl- benzamide

* SM 2-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-3-fluoro-phenyl]-5,6-dihydro-4H- pyrimidine-1-carboxylic acid1-acetoxy-2-methyl-propyl ester

*** SN 2-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-3-fluoro-phenyl]-5,6-dihydro-4H- pyrimidine-1-carboxylic acid 1-acetoxy-ethylester

** SO 2-{3-Methoxy-2-[2-(2- methoxy-phenyl)-ethyl]- phenyl}-1,4,5,6-tetrahydro-pyrimidine

** SP 3-(5-Bromo-2-methoxy- phenyl)-5-chloro-3,4- dihydro-isoquinolin-1-ylamine

** SQ 2-[2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-3-(4-methoxy-benzyloxy)- phenyl]-1,4,5,6- tetrahydro-pyrimidine

** SR 2-{2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-3-chloro-phenyl}-5-methyl- 1,4,5,6-tetrahydro- pyrimidin-5-ol

*** SS 2-[(5-Bromo-2-methoxy- phenyl)-(3-piperidin-1-yl-propylamino)-methyl]-3- chloro-6-methyl-phenol

** ST 1-{2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-6- methyl-benzyl}-piperazine

*** SU 1-{2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-6-methyl-benzyl}-4-methyl- piperazine

** SV 1-{2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-6-methyl-benzyl)-piperidine

* SW {2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-6- methyl-benzyl}-diethyl-amine

** SY 3-(5-Bromo-2-methoxy- phenyl)-1,2,3,4- tetrahydro-isoquinoline

* SX 1-{2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-3-chloro-benzyl}-piperazine

** SY 1-{2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-3-chloro-benzyl}-4-methyl- piperazine

* SZ 1-{2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-3-chloro-benzyl}-piperidine

* TA {2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-3- chloro-benzyl}-diethyl-amine

** TB 2-{2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-3- chloro-phenyl)-4,5-dihydro-1H-imidazole

*** TC (1-{2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-3-chloro-benzyl}-piperidin- 2-yl)-methanol

** TD 2-{2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-3-propoxy-phenyl}-1,4,5,6- tetrahydro-pyrimidine

*** TE 1-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-benzyl]-4-methyl-piperazine

* TF 1-{2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-6-chloro-benzyl}-piperazine

** TG 1-{2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-6-chloro-benzyl}-4-methyl- piperazine

* TH 1-{2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-6-chloro-benzyl}-piperidine

* TI {2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-6- chloro-benzyl}-diethylamine

* TJ 1-(5-Bromo-2-methoxy- benzyl)-2-(4-methoxy- benzyl)-2,3-dihydro-1H-isoindole

* TK 2-{2-[2-(5-Bromo-2-methoxy- phenyl)-ethyl]-3-chloro-phenyl}-5,6-dihydro-4H-pyrimidine-1- carboxylic acid 1-acetoxy- ethyl ester

*** TL 1-(2-{2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-3-chloro-phenyl}-5,6- dihydro-4H-pyrimidin-1- yl)-ethanone

*** TM 1-{2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-3-fluoro-benzyl)-4-methyl- piperazine

*** TN {2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-3-fluoro-benzyl}-diethyl- amine

*** TO 1-{2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-3-fluoro-benzyl}-piperidine

** TP (1-{2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-3-fluoro-benzyl}-piperidin-2- yl)-methanol

** TQ 4-Fluoro-N-{2-[4-(2- methoxy-phenyl)- piperazin-1-yl]-ethyl}-N-pyridin-2-yl-benzamide

* TR 3-(5-Bromo-2-methoxy- phenyl)-2-methyl-1,2,3,4-tetrahydro-isoquinoline

* TS 2-{2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-3-chloro-phenyl}-1-ethyl- 4,5-dihydro-1H-imidazole

*** TT {2-[3-(5-Bromo-2- methoxy-phenyl)-3,4- dihydro-1H-isoquinolin-2-yl]-ethyl}-diethyl-amine

* TU 1-(2-{2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5- dihydro-imidazol-1-yl)- ethanone

* TV 2-{2-[2-(5-Bromo-2-methoxy- phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-imidazole-1- carboxylic acid ethyl ester

* TW 2-{2-[2-(5-Bromo-2-methoxy- phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-imidazole-1- carboxylic acid isobutyl ester

* TX 2-{2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro- imidazole-1-carboxylic acid tert-butyl ester

* TY 1-(2-{2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro- imidazol-1-yl)-2,2-dimethyl- propan-1-one

** TZ [1-(5-Bromo-2-methoxy- benzyl)-indan-2-yl]- dimethyl-amine

* UA 1-(5-Bromo-2-methoxy- benzyl)-2,3-dihydro-1H- isoindole

* UB 1-(2-Methoxy-benzyl)-2- methyl-2,3-dihydro-1H- isoindole

* UC 2-Methyl-1-naphthalen-1- ylmethyl-2,3-dihydro-1H- isoindole

* UD 1-{2-[3-Chloro-2-(2- naphthalen-1-yl-ethyl)- phenyl]-4,5-dihydro-imidazol-1-yl}-2,2- dimethyl-propan-1-one

* UE {2-[1-(5-Bromo-2- methoxy-benzyl)-1,3- dihydro-isoindol-2-yl]-ethyl}-diethyl-amine

** UF 2-[3-Chloro-2-(2- naphthalen-1-yl-ethyl)-phenyl]-1-methyl-1,4,5,6- tetrahydro-pyrimidine

*** UG 2-[3-Chloro-2-(2- naphthalen-1-yl-ethyl)- phenyl]-5,6-dihydro-4H-pyrimidine-1-carboxylic acid tert-butyl ester

*** UH 2-[3-Chloro-2-(2- naphthalen-1-yl-ethyl)- phenyl]-4,5-dihydro-1H-imidazole

*** UI 1-{2-[3-Chloro-2-(2- naphthalen-1-yl-ethyl)- phenyl]-4,5-dihydro-imidazol-1-yl}-ethanone

* UJ 2-[3-Chloro-2-(2- naphthalen-1-yl-ethyl)- phenyl]-4,5-dihydro-imidazole-1-carboxylic acid isobutyl ester

* UK 2-[3-Chloro-2-(2- naphthalen-1-yl-ethyl)- phenyl]-4,5-dihydro-imidazole-1-carboxylic acid tert-butyl ester

* UL 2-[3-Chloro-2-(2- naphthalen-1-yl-ethyl)- phenyl]-4,5-dihydro-imidazole-1-carboxylic acid ethyl ester

* UM 2-[2-(5-Bromo-2-methoxy- phenyl)-ethyl]-N-(3-formylamino-propyl)-6- methyl-benzamide

* UN 2-[3-Chloro-2-(2- naphthalen-1-yl-ethyl)- phenyl]-1-ethyl-4,5-dihydro-1H-imidazole

*** UO 1-(2-{2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-3-chloro-phenyl}-5,6-dihydro-4H- pyrimidin-1-yl)-2,2-dimethyl-propan-1-one

* UP 2-{2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]- thiophen-3-yl}-4,5-dihydro-1H-imidazole

*** UQ 2-{2-[2-(5-Bromo-2-methoxy- phenyl)-ethyl]-3-chloro-phenyl-5,6-dihydro-4H-pyrimidine-1- carboxylic acid isobutyl ester

* UR 2-{2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-3- chloro-phenyl)-1-isocyanomethyl-4,5- dihydro-1H-imidazole

*** US 2-{2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-thiophen-3-yl}-1-methyl- 4,5-dihydro-1H-imidazole

*** UT 2-{2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-thiophen-3-yl}-1-ethyl-4,5- dihydro-1H-imidazole

*** UU 3-(5-Bromo-2-methoxy- benzyl)-2-methyl-2,3-dihydro-isoindol-1-one

* UX 4-(2-Methoxy-benzyl)-2- (4-methoxy-benzyl)- 1,2,3,4-tetrahydro-isoquinoline

* UW 4-(5-Bromo-2-methoxy- benzyl)-2-(4-methoxy- benzyl)-1,2,3,4-tetrahydro-isoquinoline

* UY 2-{2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-3-chloro-phenyl}-1-propyl- 4,5-dihydro-1H-imidazole

*** UZ 2-{2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-3- chloro-phenyl}-3a,4,5,6,7,7a-hexahydro- 1H-benzoimidazole

*** VA 5,5-Dimethyl-2-[2- (naphthalen-1- ylsulfanylmethyl)-phenyl]-4,5-dihydro-1H-imidazole

*** VB 2-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-3-chloro-phenyl]-4,4-dimethyl-4,5- dihydro-1H-imidazole

*** VC N-(5-Bromo-2-methoxy- benzyl)-N′-methyl-N- naphthalen-1-ylmethyl-ethane-1,2-diamine

** VD 2-{2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-3-chloro-phenyl}-1-ethyl- 1,4,5,6-tetrahydro- pyrimidine

*** VE 2-[2-(5-Bromo-2-methoxy- phenyl)-ethyl]-3-chloro-N,N,N′-trimethyl- benzamidine

*** VF 2-[3-Chloro-2-(2- naphthalen-1-yl-ethyl)- phenyl]-1-methyl-4,5-dihydro-1H-imidazole

*** VG 1-Benzyl-2-{2-[2-(5- bromo-2-methoxy- phenyl)-ethyl]-3-chloro-phenyl}-4,5-dihydro-1H- imidazole

*** VH ({2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-3-chloro-phenyl}-pyrrolidin- 1-yl-methylene)-methyl- amine

** VI 2-{2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-3- chloro-phenyl}-1-isopropyl-4,5-dihydro-1H- imidazole

*** VJ 2-{2-[2-(5-Bromo-2- methoxy-phenyl)-ethyl]-3-chloro-phenyl}-1-(2,2,2- trifluoro-ethyl)-4,5- dihydro-1H-imidazole

*** VK 1-{2-[2-(5-Bromo-2- methoxy-benzylsulfanyl)- benzyloxy]-ethyl}-aziridine

* VL 3-[2-(5-Bromo-2-methoxy- benzylsulfanyl)-benzylamino]-3-methyl-butan-1-ol

* VM 3-Cyano-N-(2- dimethylamino-ethyl)-N- naphthalen-1-ylmethyl-benzamide

* VN N-(2-Dimethylamino- ethyl)-4-fluoro-N- naphthalen-1-ylmethyl-benzenesulfonamide

* VO 2-Cyano-N-(2- dimethylamino-ethyl)-N- naphthalen-1-ylmethyl-benzenesulfonamide

* VP 2-[2-(Naphthalen-1- ylsulfanylmethyl)- pyrrolidin-1-yl]-ethyl-1-pyrrolidine

* VQ C-{1-(2-Naphthalen-1-yl- ethyl)-pyrrolidin-2-yl]-methyl-1-pyrrolidine

* VR 1-(2-Naphthalen-1-yl- ethyl)-piperidine-2- carboxylic acid methylester

* VS (1-Ethyl-pyrrolidin-2- ylmethyl)-naphthalen-2-ylmethyl-naphthalen-1- ylmethyl-amine

* VT (3-Bromo-benzyl)-(3- imidazol-1-yl-propyl)- naphthalen-1-ylmethylamine

* VU 6-[2-(Cyclohexyl-methyl- amino)-ethyl]-2-oxo-2,3-dihydro-benzoimidazole-1- carboxylic acid benzylamide

* VV (5-Bromo-2-methoxy- benzyl)-(3-imidazol-1-yl- propyl)-naphthalen-1-ylmethyl-amine

* VW (3-Imidazol-1-yl-propyl)- naphthalen-2-ylmethyl-naphthalen-1-ylmethyl- amine

* VX Dimethyl-[1-(2- naphthalen-1-yl-ethyl)- piperidin-2-ylmethyl]-amine

* VY [2-(Naphthalen-1- ylmethylsulfanyl)-phenyl]- carbamic acid 2-dimethylamino-ethyl ester

* VZ 3-(5-Bromo-2-methoxy- benzyloxy)-1-(2- pyrrolidin-1-yl-ethyl)-piperidine

* WA C-[1-(2-Naphthalen-1-yl- ethyl)-piperidin-2-yl]-methyl-N-piperidine

* WB 1-[1-(2-Naphthalen-1-yl- ethyl)-piperidin-2-ylmethyl]-1H-pyrrole-2- carbonitrile

* WC 1-[2-(Naphthalen-1- ylsulfanylmethyl)- pyrrolidin-1-yl]-2-pyrrolidin-1-yl-ethanone

* WD 1-{2-[2-(Naphthalen-1- ylsulfanylmethyl)- pyrrolidin-1-yl]-ethyl}-piperidine

* WE 3-(5-Bromo-2-methoxy- benzyloxy)-piperidine

* WF 5-(Naphthalen-1- ylsulfanylmethyl- pyrrolidin-2-one

* WG 5-(Naphthalen-1- ylsulfanylmethyl)-1-(2- pyrrolidin-1-yl-ethyl)-pyrrolidin-2-one

* WH 2-[3-(5-Bromo-2-methoxy- benzyloxy)-pyrrolidin-1-yl]-ethyl-1,N-pyrrolidine

* WI 2-{[(3-Bromo-benzyl)- naphthalen-1-ylmethyl-amino]-methyl}-piperidine 1-carboxylic acid tert- butyl ester

* WJ 4-(2-Methoxy-benzyl)-2- (4-methoxy-benzyl)- 1,2,3,4-tetrahydro-isoquinoline

* WK 4-(5-Bromo-2-methoxy- benzyl)-2-(4-methoxy- benzyl)-1,2,3,4-tetrahydro-isoquinoline

*

[1826] TABLE 5 Molecular Salt Weight Structure Parent 347.5242

Parent 331.9091

Parent 333.4453

Parent 365.4626

Parent 646.0503

Formate 513.4192

Formate 533.4937

Formate 595.5646

HCl 525.9799

Formate 530.4901

Parent 466.6471

Parent 508.7277

Parent 377.3244

Parent 378.5383

Parent 406.5921

Parent 348.4882

Parent 404.5762

Parent 312.4552

Parent 348.4882

Parent 328.4546

Formate 599.6367

Formate 579.5194

Formate 590.5457

Formate 568.4987

Formate 535.5096

Parent 561.5456

Formate 559.5316

Formate 534.4815

Formate 507.4559

Formate 493.429

Parent 591.6153

Parent 372.3079

Parent 377.3244

Parent 337.2916

Parent 458.6678

Parent 353.5078

Parent 362.4717

Formate 468.5781

Formate 527.4406

Formate 468.5781

Formate 502.8609

Formate 516.8877

Parent 527.5285

Formate 483.4339

Parent 178.2774

Parent 426.1942

Parent 392.2957

Parent 649.6519

Formate 333.2297

Formate 595.5646

Parent 377.3244

Parent 298.4283

Parent 404.5762

Formate 482.605

Parent 321.2376

Parent 454.6122

Parent 513.4747

Parent 432.9709

Parent 467.449

Parent 382.5267

Parent 398.5261

HCl 451.0753

HCl 418.0454

HCl 443.0552

Parent 447.6446

Parent 402.5603

Parent 549.5346

Formate 581.5377

Formate 443.3691

Formate 485.4497

Formate 523.4986

Formate 457.396

Formate 529.4595

Formate 338.4082

Formate 340.3808

HCl 442.024

Parent 508.4765

Parent 508.4765

Parent 522.5034

Parent 522.5034

Parent 522.5034

Parent 428.5524

Parent 374.528

Parent 387.5029

Parent 294.4399

Parent 353.3024

Formate 336.3924

Parent 293.4118

Parent 336.4003

Parent 318.4619

Parent 378.4742

Parent 406.528

Parent 464.4051

Parent 364.4473

Formate 400.5463

Parent 430.5902

Not Determined

HCl 472.873

Formate 467.388

Parent 278.3538

Parent 282.4289

Parent 296.4558

Formate 443.3855

Parent 336.5206

Parent 343.4717

Not Determined

Not Determined

Not Determined

EXAMPLE 5 cAMP Assay for MC4-R Antagonist Activity

[1827] Method

[1828] MC4 Receptors are expressed in stably transfected K293 cells. Thecells are incubated in DMEM base medium (10% FBS, 1× glutamine, and 0.4mg/ml G418) at 37° C., in an atmosphere of 6.0% CO₂ and 90% relativehumidity. Two days before the experiment, the cells are trypsinized and200 μl of the cell suspension (138,000 cells/ml) is deposited into96-well Costar cell culture plates.

[1829] The test compounds are then dissolved in DMSO creating a 30 mMstock solution, which is subsequently diluted to 180, 650, 20, 6.6, 2.2μM in OPTI-MEM (GIBCO-BRL) media with 50 μM IBMX(isobutylmethylxanthine, Sigma) minutes before the experiment.

[1830] The media is then thoroughly removed from the cell culture platesthrough a 12-channel straight manifold. 90 μl of OPTI-MEM media with 50μM IBMX is added to each well (McHale et al. FEBS Letters 345 (1994)147-150). The plate is then placed in an incubator set at 37° C., 6.0%CO₂ and 90% relative humidity. After 15 minutes of incubation, 90 μl ofthe test compound solutions (or a control solution of OPTI-MEM and IBMX)are added and the plates are incubated for another 10 minutes. 20 μl ofthe ligand MSH solution in OPTI-MEM is then added. The cell plates areincubated for an additional hour at 37° C.

[1831] After the incubation, the media mixture is removed by 12-channelstraight manifold. 60 μl of 70% ethanol is added to each well. Theplates are then placed on a shaker for 30 minutes to extract the cAMP.The amount of cAMP is detected by the cyclic AMP [125I] Biotrak SPAscreening assay system (Amersham). The system involves adding 50 μl of1× assay buffer into each well of an OptiPlate-96 (Packard). 50 μl ofthe tracer solution (cAMP-¹²⁵I) is added into each well. 5μl of the cAMPextract is added into the mixture, followed by the addition of cAMPantiserum and 50μl of SPA PVT-antibody binding beads. The plates arethen covered with TopSeal-A (Parkard) and incubated at room temperaturefor up to fifteen hours before being analyzed using a TOPCOUNT machine.

[1832] Compounds O, N, AG, AL, and AM were found to be at least 100 foldmore selective for MC4-R than MC1-R, MC3-R and MC5-R.

EXAMPLE 6 In Vivo Assay for MC4-R Antagonist Activity

[1833] The following in vivo assay was used to test the effects of MC4-Rantagonists on mice.

[1834] Male lean C57BL/6J mice were individually housed in macroloncages (22±2 C.°; 12:12 h light/dark cycle with lights off at 6 pm). Tapwater and mouse chow diet were given ad libitum. Mice werestereotaxically implanted with a chronic guide cannula aimed to thethird ventricle (intracerabroventricular) one week prior to testing.

[1835] It had been previously determined that food deprived lean micewhich had been injected with 0.1 nmol of MT II (a MC4-R agonist) priorto refeeding showed decreased feeding response within 1 hour ofinjection (FIG. 1). In previous experiments using peptidic MC4-Rantagonists, it has been shown that the decreased feeding response of MTII treated food-deprived mice can be reversed by theintracerabroventricular injection of MC4-R antagonists.

[1836] In this experiment, food deprived lean mice were injectedintracerabroventricularly with either Compound N or Compound O, at adose of 15 nmol prior to injection of MT II at the dose of 0.05 nmol.

[1837] The results of the experiment are shown in FIGS. 2 and 3. FIG. 2shows that administration of 15 nmol of Compound N partially reversesthe effect of the administration of the MC4-R agonist, MT II. FIG. 3shows that administration of Compound O did not significantly effect thefood intake of mice treated with MT II.

EXAMPLE 7 cAMP Assay for MC Receptor Agonist Activity (cAMP Assay)

[1838] The cAMP assay identifies compounds which have agonist activityagainst MC receptors. It is used to identify the selectivity of agonistwhich selectively antagonize receptors of interest. The following methodis outlined for MC4-R, but corresponding procedures were used for theother MC receptors, MC1-R, MC3-R, and MC5-R.

[1839] Method

[1840] MC4 Receptors are expressed in stably transfected HEK293 cells.The cells are incubated in DMEM base medium (10% FBS, 1× glutamine, and0.4 mg/ml G418) at 37° C., in an atmosphere of 6.0% CO₂ and 90% relativehumidity. Two days before the experiment, the cells are trypsinized and200 μl of the cell suspension (138,000 cells/ml) is deposited into96-well Costar cell culture plates.

[1841] The test compounds are then dissolved in DMSO creating a 30 mMstock solution, which is subsequently diluted to 180, 650, 20, 6.6, 2.2μM in OPTI-MEM (GIBCO-BRL) media with 50μM IBMX (isobutylmethylxanthine,Sigma) minutes before the experiment.

[1842] The media is then thoroughly removed from the cell culture platesthrough a 12-channel straight manifold. 90 μl of OPTI-MEM media with 50μM IBMX is added to each well (McHale et al. FEBS Letters 345 (1994)147-150). The plate is then placed in an incubator set at 37° C., 6.0%CO₂ and 90% relative humidity. After 15 minutes of incubation, 90 μl ofthe test compound solutions (or a control solution of OPTI-MEM and IBMX)are added and the plates are incubated for another 10 minutes. 20 μl ofthe ligand MSH solution in OPTI-MEM is then added. The cell plates areincubated for an additional hour at 37° C.

[1843] After the incubation, the media mixture is removed by 12-channelstraight manifold. 60 μl of 70% ethanol is added to each well. Theplates are then placed on a shaker for 30 minutes to extract the cAMP.The amount of cAMP is detected by the cyclic AMP [¹²⁵I] Biotrak SPAscreening assay system (Amersham). The system involves adding 50 μl of1× assay buffer into each well of an OptiPlate-96 (Packard). 50 μl ofthe tracer solution (cAMP-¹²⁵I) is added into each well. 5 μl of thecAMP extract is added into the mixture, followed by the addition of cAMPantiserum and 50 μl of SPA PVT-antibody binding beads. The plates arethen covered with TopSeal-A (Packard) and incubated at room temperaturefor up to fifteen hours before being analyzed using a TOPCOUNT machine.

[1844] Incorporation by Reference

[1845] The entire contents of all references and patents cited hereinare hereby incorporated by reference. The entire contents of U.S. Pat.5,908,609 and all its references also expressly incorporated herein.

[1846] Equivalents

[1847] Those skilled in the art will recognize, or be able to ascertainusing no more than routine experimentation, many equivalents to thespecific embodiments and methods described herein. Such equivalents areintended to be encompassed by the scope of the following claims.

What is claimed is:
 1. A compound of formula XVII:

or a pharmaceutically acceptable salt thereof, wherein: P¹, P², P³, andP⁴ are each selected from a substituted or unsubstituted carbon, whereinone of P¹-P⁴ is optionally replaced by a nitrogen atom, or the ringbearing P¹-P⁴ is a thiophene ring, wherein P³-P⁴ together are replacedby a sulfur atom; Z¹ is CH or a carbon substituted with R⁷; Z² is CH ora carbon substituted with R⁸; Z³, Z⁴ and Z⁵ are each independentlyselected from CH or a carbon substituted with R⁹; R⁷ is C₁₋₃ alkoxy,C₁₋₃ haloalkoxy, cyano, C₁₋₃ cyanoalkyl, halo, C₁₋₃ alkyl, or C₁₋₃haloalkyl; R⁸ is halo, C₁₋₃ alkyl, C₁₋₃ haloalkyl, or R⁷ and R⁸ aretaken together with their intervening atoms to form a fused, 5-6membered aromatic or nonaromatic ring having 0-2 ring heteroatomsselected from oxygen, nitrogen or sulfur; each R⁹ is independentlyselected from halo, cyano, trialkylsiloxy, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆ alkenyl, C₁₋₆ alkynyl, N(R¹⁰)₂, (C₁₋₆alkyl)-N(R¹⁰)₂, O(C₁₋₆ alkyl)-N(R¹⁰)₂, C₁₋₆ alkylsulfonyl, C₁₋₆alkylthio, or phenyl, or two R⁹ on neighboring carbons are takentogether to form a fused, 5-6 membered aromatic or nonaromatic ringhaving 0-2 ring heteroatoms selected from oxygen, nitrogen, or sulfur;each R¹⁰ is independently selected from hydrogen, C₁₋₄ alkyl, or two R¹⁰on the same nitrogen are taken together with their intervening nitrogento form a 5-6 membered ring having 1-2 ring heteroatoms selected fromoxygen, nitrogen or sulfur; L₂ is a covalent bond, a substituted orunsubstituted 1-2 carbon chain or a 2 carbon carbonyl chain, wherein oneof the carbons along with the hydrogen attached thereto is optionallyreplaced by oxygen, N(R¹⁰), or sulfur; t is CH₂, CHR³, or CR³R⁴, and sis CH₂, CHR⁵, or CR⁵R⁶, or t-s taken together is CH═CH, CR³═CH, CH═CR⁵or CR³═CR⁵; R³, R⁴, R⁵, and R⁶ are each independently selected from C₁₋₄alkyl, C₁₋₄ alkylcarboxyl, C₁₋₄ alkoxycarbonyl, C₁₋₄ alkylcarboxamide,or two of R³, R⁴, R⁵, and R⁶ are taken together with their interveningatom or atoms to form a fused 3-7 membered aromatic or non-aromatic or3-7 membered spirocyclic ring, having 0-2 ring heteroatoms selected fromoxygen, nitrogen or sulfur; R is hydrogen or a C₁₋₈ alkyl or C₁₋₈alkylcarbonyl that is substituted with 0-2 R¹¹, or R and R⁵ are takentogether with their intervening atoms to form a fused pyrrolidino orpiperidino ring, or R and L₂ are taken together with their interveningatoms to form a fused five membered ring having 1-2 ring heteroatomsselected from oxygen, nitrogen or sulfur; each R¹¹ is independentlyselected from C₁₋₃ alkyl, cyano, halo, haloalkyl, N(R¹⁰)₂, (C═O)N(R¹⁰)₂,OC(═O)N(R¹⁰)₂, OH, S(C₁₋₆ alkyl), SO₂(C₁₋₆ alkyl), SO₂N(R¹⁰)₂, C₁₋₆alkoxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkylcarboxyl, C₁₋₆ alkoxycarboxyl,C₅₋₆ aryl, C₆₋₁₀ arylalkyl, or a 3-6 membered heterocyclyl having 1 or 2heteroatoms.
 2. The compound of claim 1 wherein P¹, P², P³ and P⁴ areeach selected from a substituted or unsubstituted carbon.
 3. Thecompound of claim 2 having one or more features selected from the groupconsisting of: (a) Z¹ is a carbon substituted with R⁷; (b) Z², Z³ and Z⁵are each CH; (c) Z⁴ is a carbon substituted with R⁹; (d) L₂ is acovalent bond; (e) t is CH₂; (f) s is CH₂; and (g) R is hydrogen or C₁-8alkyl that is substituted with 0-2 R¹¹.
 4. The compound of claim 3wherein: (a) Z¹ is a carbon substituted with R⁷; (b) Z², Z³ and Z⁵ areeach CH; (c) Z⁴ is a carbon substituted with R⁹; (d) L² is a covalentbond; (e) t is CH₂; (f) s is CH₂; and (g) R is hydrogen or C₁₈ alkylthat is substituted with 0-2 R¹¹.
 5. The compound of claim 3 having oneor more features selected from the group consisting of: (a) P¹, P², andP³ are each an unsubstituted carbon, and P⁴ is an unsubstituted carbon,or a carbon substituted with a halogen or alkoxy; (b) R⁷ is alkoxy; (c)R⁹ is halo, cyano or alkynyl; and (d) R is hydrogen, or C₁₋₄ alkyl thatis substituted with 0-2 R¹¹, wherein each R¹¹ is independently selectedfrom C₁₋₃ alkyl, cyano, halo, C₁₋₄ alkoxy, or a 5-6 memberedheterocyclyl having 1 or 2 heteroatoms.
 6. The compound of claim 4wherein: (a) P¹, P², and P³ are each an unsubstituted carbon, and P⁴ isan unsubstituted carbon, or a carbon substituted with a halogen oralkoxy; (b) R⁷ is alkoxy; (c) R⁹ is halo, cyano or alkynyl; and (d) R ishydrogen, or C₁₋₄ alkyl that is substituted with 0-2 R¹¹, and each R¹¹is independently selected from C₁₋₃ alkyl, cyano, halo, C₁₋₄ alkoxy, ora 5-6 membered heterocyclyl having 1 or 2 heteroatoms.
 7. The compoundof claim 2 having one or more features selected from the groupconsisting of: (a) Z¹ is a carbon substituted with R⁷, Z² is a carbonsubstituted with R⁸, and R⁷ and R⁸ are taken together to form a fused,5-6 membered aromatic or nonaromatic ring having 0-2 ring heteroatomsselected from oxygen, nitrogen or sulfur; (b) Z³ and Z⁵ are each CH; (c)Z⁴ is a carbon substituted with R⁹; (d) L² is a covalent bond; (e) t isCH₂; (f) s is CH₂; and (g) R is hydrogen or C₁₋₈ alkyl that issubstituted with 0-2 R¹¹.
 8. The compound of claim 7 wherein: (a) Z¹ isa carbon substituted with R⁷, Z² is a carbon substituted with R⁸, and R⁷and R⁸ are taken together to form a fused, 5-6 membered aromatic ornonaromatic ring having 0-2 ring heteroatoms selected from oxygen,nitrogen or sulfur; (b) Z³ and Z⁵ are each CH; (c) Z⁴ is a carbonsubstituted with R⁹; (d) L² is a covalent bond; (e) t is CH₂; (f) s isCH₂; and (g) R is hydrogen or C₁₋₈ alkyl that is substituted with 0-2R¹¹.
 9. The compound of claim 7 having one or more features selectedfrom the group consisting of: (a) P¹, P², and P³ are each anunsubstituted carbon, and P⁴ is an unsubstituted carbon, or a carbonsubstituted with a halogen or alkoxy; (b) R⁷ and R⁸ are taken togetherto form a substituted or unsubstituted benzo, furano, thieno, dioxoloring. (c) R⁹ is halo, cyano or alkynyl; and (d) R is hydrogen, or C₁₋₄alkyl that is substituted with 0-2 R¹¹, and each R¹¹ is independentlyselected from C₁₋₃ alkyl, cyano, halo, C₁₋₄ alkoxy, or a 5-6 memberedheterocyclyl having 1 or 2 heteroatoms.
 10. The compound of claim 8wherein: (a) P¹, P², and P³ are each an unsubstituted carbon, and P⁴ isan unsubstituted carbon, or a carbon substituted with a halogen oralkoxy; (b) R⁷ and R⁸ are taken together to form a substituted orunsubstituted benzo, furano, thieno, dioxolo ring. (c) R⁹ is halo, cyanoor alkynyl; and (d) R is hydrogen, or C₁₋₄ alkyl that is substitutedwith 0-2 R¹¹, and each R¹¹ is independently selected from C₁₋₃ alkyl,cyano, halo, C₁₋₄ alkoxy, or a 5-6 membered heterocyclyl having 1 or 2heteroatoms.
 11. The compound of claim 2 having one or more featuresselected from the group consisting of: (a) Z¹ is a carbon substitutedwith R⁷; (b) Z², Z³ and Z⁵ are each CH; (c) Z⁴ is a carbon substitutedwith R⁹; (d) L² is a covalent bond; (e) t is CH₂ or CHR³; (f) s is CHR⁵,or CR⁵R⁶, and (g) R is hydrogen or C₁₋₈ alkyl that is substituted with0-2 R¹¹; wherein R³ and R⁵ are optionally taken together with theirintervening atom or atoms to form a fused 3-7 membered aromatic ornon-aromatic ring or R and R⁵ are optionally taken together with theirintervening atoms to form a fused pyrrolidino or piperidino ring. 12.The compound of claim 11 wherein: (a) Z¹ is a carbon substituted withR⁷; (b) Z², Z³ and Z⁵ are each CH; (c) Z⁴ is a carbon substituted withR⁹; (d) L² is a covalent bond; (e) t is CH₂ or CHR³; (f) sis CHR⁵, orCR⁵R⁶, (g) R is hydrogen or C₁₋₈ alkyl that is substituted with 0-2 R¹¹,wherein R³ and R⁵ are optionally taken together with their interveningatom or atoms to form a fused 3-7 membered aromatic or non-aromatic ringor R and R⁵ are optionally taken together with their intervening atomsto form a fused pyrrolidino or piperidino ring.
 13. The compound ofclaim 11 having one or more features selected from the group consistingof: (a) P¹, P², and P³ are each an unsubstituted carbon, and P⁴ is anunsubstituted carbon, or a carbon substituted with a halogen or alkoxy;(b) R⁷ is alkoxy; (c) R⁹ is halo, cyano or alkynyl; and (d) s is CHR⁵,wherein R⁵ is taken together with R³ to form a fused 5-6 memberednon-aromatic ring, or R⁵ is taken together with R with their interveningatoms to form a fused pyrrolidino or piperidino ring.
 14. The compoundof claim 12 wherein: (a) P¹, P², and P³ are each an unsubstitutedcarbon, and P⁴ is an unsubstituted carbon, or a carbon substituted witha halogen or alkoxy; (b) R⁷ is alkoxy; (c) R⁹ is halo, cyano or alkynyl;and (d) s is CHR⁵, wherein R⁵ is taken together with R³ to form a fused5-6 membered non-aromatic ring, or R⁵ is taken together with R withtheir intervening atoms to form a fused pyrrolidino or piperidino ring.15. The compound of claim 2 having one or more features selected fromthe group consisting of: (a) Z¹ is a carbon substituted with R⁷, Z² is acarbon substituted with R⁸, and R⁷ and R⁸ are taken together to form afused, 5-6 membered aromatic or nonaromatic ring having 0-2 ringheteroatoms selected from oxygen, nitrogen or sulfur; (b) Z³ and Z⁵ areeach CH; (c) Z⁴ is a carbon substituted with R⁹; (d) L₂ is a covalentbond; (e) t is CH₂ or CHR³; (f) s is CUR⁵, or CR⁵R⁶, wherein R³ and R⁵are optionally taken together with their intervening atom or atoms toform a fused 3-7 membered aromatic or non-aromatic ring; and (g) R ishydrogen or C₁₋₈ alkyl that is substituted with 0-2 R¹¹, or R and R⁵ aretaken together with their intervening atoms to form a fused pyrrolidinoor piperidino ring.
 16. The compound of claim 15 wherein: (a) Z¹ is acarbon substituted with R⁷, Z² is a carbon substituted with R⁸, and R⁷and R⁸ are taken together to form a fused, 5-6 membered aromatic ornonaromatic ring having 0-2 ring heteroatoms selected from oxygen,nitrogen or sulfur; (b) Z³ and Z⁵ are each CH; (c) Z⁴ is a carbonsubstituted with R⁹; (d) L² is a covalent bond; (e) t is CH₂ or CHR³;(f) s is CHR⁵, or CR⁵R⁶, wherein R³ and R⁵ are optionally taken togetherwith their intervening atom or atoms to form a fused 3-7 memberedaromatic or non-aromatic ring; and (g) R is hydrogen or C₁₋₈ alkyl thatis substituted with 0-2 R¹¹, or R and R⁵ are taken together with theirintervening atoms to form a fused pyrrolidino or piperidino ring. 17.The compound of claim 15 having one or more features selected from thegroup consisting of: (a) P¹, P², and P³ are each an unsubstitutedcarbon, and P⁴ is an unsubstituted carbon, or a carbon substituted witha halogen or alkoxy; (b) R⁷ and R⁸ are taken together to form asubstituted or unsubstituted benzo, furano, thieno, dioxolo ring. (c) R⁹is halo, cyano or alkynyl; and (d) s is CHR⁵, wherein R⁵ is takentogether with R³ to form a fused 5-6 membered non-aromatic ring, or R⁵is taken together with R with their intervening atoms to form a fusedpyrrolidino or piperidino ring.
 18. The compound of claim 16 wherein:(a) P¹, P², and P³ are each an unsubstituted carbon, and P⁴ is anunsubstituted carbon, or a carbon substituted with a halogen or alkoxy;(b) R⁷ and R⁸ are taken together to form a substituted or unsubstitutedbenzo, furano, thieno, dioxolo ring. (c) R⁹ is halo cyano or alkynyl;and (d) s is CHR⁵, wherein R⁵ is taken together with R³ to form a fused5-6 membered non-aromatic ring, or R⁵ is taken together with R withtheir intervening atoms to form a fused pyrrolidino or piperidino ring.19. A compound selected from the group consisting of:


20. A pharmaceutical composition comprising a compound according toclaim 1 and a pharmaceutically acceptable carrier.
 21. A method oftreating an MC4-R associated disorder in a patient in need thereofcomprising administering to said patient a compound of formula (XVII) inclaim
 1. 22. A method of treating an MC4-R associated disorder in apatient in need thereof comprising administering to said patient apharmaceutical composition comprising a compound of formula (XVII) inclaim
 1. 23. A method of treating a weight loss disorder in a subjectidentified as in need of such treatment comprising administering acompound of formula (XVII) in claim
 1. 24. The method of claim 23,wherein the weight loss disorder is a cachexia, aging involuntary weightloss, sarcopenia, catabolic wasting, or anorexia.
 25. The method ofclaim 24, wherein cachexia is cancer cachexia, cardiac cachexia, chronicillness cachexia, or AIDS cachexia.
 26. A method of inhibiting MC4-Ractivity in a patient in need thereof comprising administering to saidpatient a pharmaceutical composition comprising a compound of formula(XVII) in claim 1.